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1
Christodoulou, Kyproula. "Molecular genetics of autosomal recessive spinocerebellar ataxias." Thesis, University of London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244268.
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Nommiste, B. "A model system of autosomal-recessive bestrophinopathy." Thesis, University College London (University of London), 2016. http://discovery.ucl.ac.uk/1476812/.
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Mutations in the bestrophin 1 (BEST1) gene lead to a variety of bestrophinopathies. To identify the exact location and function of BEST1 is key to understanding the mechanisms that cause bestrophinopathies. Thus, it was decided to study autosomal-recessive bestrophinopathy (ARB), a distinct inherited bestrophinopathy caused by BEST1, a protein located in the retinal pigment epithelium (RPE), which is a monolayer of epithelial cells located at the back of the eye between the photosensitive retinal layer and the choroid. The RPE closely interacts with the photoreceptor layer. Hence, mutations in BEST1 cause the RPE to dysfunction, which in turn leads to photoreceptor degeneration and eventual blindness. The ARB mutation studied in this thesis is a pR200X mutation that is a premature stop mutation causing alteration in the RPE and subretinal deposits in the macular area. Currently, patients with bestrophinopaties, such as ARB, do not have any available treatments and loss of vision cannot be prevented. As mentioned earlier, resolving the exact location and function of the BEST1 in the RPE is a crucial step in identifying therapies for these patient groups and understanding the pathology underlying bestrophinopathies. Human induced pluripotent stem cells (hiPSCs) are a promising source of cells to model a patient-specific disease in vitro and identify potential therapies. It has been previously demonstrated that RPE could be produced from the iPSCs and human embryonic stem cells (hESCs). Thus, in order to understand the role of BEST1 in RPE cells iPSCs were created from pR200X patient fibroblasts by reprogramming with episomal vectors (C-MYC, KLF4, LIN28, OCT4 and SOX2). iPSC colonies were isolated and expanded. After optimising the stem cell culture methods for patient-specific iPSCs, the iPSCs were differentiated into RPE by a mainly spontaneous differentiation method with an initial burst of activin A. After approximately 6 weeks pigmented foci were purified by manual dissection and cells were seeded to encourage monolayer formation. Patient iPSCs and iPSC-derived RPE cells were assessed by standard molecular and cellular protocols, including immunocytochemistry, electron microscopy, western blots, PCR and teratoma assay, in comparison to the control iPSCs and iPSC-derived RPE cells. To assess any functional abnormalities in the pR200X iPSC-derived RPE cells transepithelial resistance, phagocytosis and patch-clamping experiments were performed on patient and control iPSC-derived RPE. Additionally, gene therapy was investigated as a potential therapeutic option for the bestrophinopathy patients with a premature stop mutation.
3
Virolainen, Elina. "Molecular genetics of autosomal recessive congenital ichthyosis." Helsinki : University of Helsinki, 2000. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/virolainen/.
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El-Aziz, El-Anwar Saad Mai Mohamed Abd. "Molecular genetics of autosomal recessive retinitis pigmentosa." Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1446073/.
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Autosomal recessive retinitis pigmentosa (arRP) is one of the commonest forms of monogenic retinal degeneration (RD). To date, 24 loci have been implicated in the pathogenesis of arRP. The genes for five of these loci (RP22, RP25, RP28, RP29 and RP32), still remain to be identified. This thesis mainly focused on the cloning of a major gene (RP25) however identifying novel loci for recessive RP constituted a significant objective. Originally the RP25 locus was mapped to chromosome 6pl2.1-ql5, a region that spans 34 Mb, by our collaborators in Seville in seven Spanish families. Initially, a whole-genome scan in these families was undertaken using GeneChip 10K array. The data obtained confirmed the initial findings of linkage to the RP25 region. To date, 61 out of 111 genes within the interval (-55%) have been excluded as disease causing by direct sequence analysis. A large number of single nucleotide polymorphisms (SNPs), of which a significant percentage was novel were identified. We have also postulated that both RP25 and Leber congenital amaurosis 5 (LCA5), a severe form of RD, could be due to the same genetic defect since they genetically overlap. Therefore, seventeen LCA families were genotyped to identify new LCA5 families that may further refine the RP25 interval by identifying novel crossovers. However, the gene for LCA5 has been recently cloned and sequence analysis of the RP25 families rules out this gene as causative of RP25. To investigate if copy number variations (CNVs) exist within the RP25 interval, a comparative genome hybridisation (CGH) was performed on one of the RP25 families (RP5). A clone from the tiling path, chr6tp-19C7, within 6ql2 was observed to be deleted in all affected members of this family indicating that one of the genes within this interval could be responsible for the RP25 phenotype. A novel approach utilising the 10K GeneChip for identifying the disease locus in three non-consanguineous Chinese families with arRP was implemented. The studied families were probably linked to the RP25 locus proposing that this approach could be a useful tool for genetic mapping in cases of rare and genetically heterogeneous recessive traits. Finally, in parallel, a genomewide linkage search in a consanguineous family with arRP was undertaken. Linkage to a 10-cM interval on chromosome 10q23.1-23.3 was observed where a good candidate gene, protocadherin-21 (PCDH21), is located. A homozygous 1-bp deletion was identified in this family in addition to two other novel mutations in two different patients raising the possibility that PCDH21 is likely to be a novel gene for RP.
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Kurian, Manju Ann. "Molecular genetic investigation of autosomal recessive neurodevelopmental disorders." Thesis, University of Birmingham, 2010. http://etheses.bham.ac.uk//id/eprint/1126/.
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Development of the human brain occurs in a number of complex pre- and postnatal stages which are governed by both genetic and environmental factors. Aberrant brain development due to inherited defects may result in a wide spectrum of neurological disorders which are commonly encountered in the clinical field of paediatric neurology. In the work for this thesis, I have investigated the molecular basis and defined the clinical features of three autosomal recessive neurological syndromes. I studied a cohort of children with early onset epileptic encephalopathy and, in one family, identified a novel homozygous pathogenic mutation of PLCB1. I have also utilised autozygosity mapping techniques to study consanguineous families with a complex motor disorder, infantile parkinsonism-dystonia, and identified loss-of function mutations in the gene encoding the dopamine transporter (SLC6A3). Subsequent acquisition of a cohort of similarly affected children allowed detailed clinical and molecular characterisation of this novel disorder, dopamine transporter deficiency syndrome. Finally I have delineated the clinical and genetic features of PLA2G6-associated neurodegeneration. The identification of disease-causing genes contributes greatly to understanding the disease mechanisms underlying such early-onset disorders, and also provides novel insights into normal human neurodevelopment.
6
Alsaedi, Atif Saud. "Exome sequencing analysis of rare autosomal recessive disorders." Thesis, University of Birmingham, 2017. http://etheses.bham.ac.uk//id/eprint/7700/.
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Since the human genome project was completed in 2003, extraordinary progress has been made in the field of genomics with the development of new sequencing technologies and the widespread introduction of next generation sequencing (NGS). The application of NGS initiated a new era in genomics by massively increasing the number and diversity of the sequenced genomes at lower cost. Human Molecular Genetics has greatly benefited from the use of NGS-based strategies to identify human disease genes. In this thesis, I investigated the application of genetic techniques to investigate the molecular basis of autosomal recessively inherited disorders of unknown etiology. A range of disease phenotypes, including oligodontia and fetal akinesia/multiple pterygium syndrome (FA/MPS), were investigated in patient cohorts that included many cases with parental consanguinity. Using an autozygosity linkage analysis-based approach and Sanger sequencing of candidate genes resulted in the identification germline RYR1 mutations in FA/MPS. Subsequently, using exome sequencing techniques, the molecular basis of FA/MPS was further elucidated by the identification of germline mutations in RYR1, NEB, CHRNG, CHRNA1 and TPM2. The application of NGS in genetically heterogeneous disorders such as fetal akinesia/multiple pterygium syndrome can enable better and less expensive molecular diagnostic services aimed at specific mutation spectra, though more extensive sequencing can lead to the identification of larger numbers of variants of uncertain significance.
7
Talbot, Kevin. "The molecular pathogenesis of autosomal recessive spinal muscular atrophy." Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300137.
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Sergouniotis, P. I. "Genetic and phenotypic heterogeneity in autosomal recessive retinal disease." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1352445/.
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Molecular genetics has transformed our understanding of disease and is gradually changing the way medicine is practiced. Genetic mapping provides a powerful approach to discover genes and biological processes underlying human disorders. Recent advances in DNA microarray and sequencing technology have significantly increased the power of genetic mapping studies and have ushered in a new era for biomedicine. In this thesis, linkage analysis (including homozygosity mapping), exome sequencing and candidate gene sequencing have been utilised to genetically dissect autosomal recessive retinal disease. Subsequently, clinical findings from patients found to be similar in terms of molecular pathology have been pooled. DNA and basic phenotypic data from over 500 unrelated individuals were available for the project. Disease-causing variants in three genes that have not been previously associated with human recessive disorders are reported: (a) biallelic mutations in TRPM1 abrogate ON bipolar cell function and cause complete congenital stationary night blindness; (b) biallelic mutations in KCNJ13, a gene encoding an inwardly rectifying potassium channel subunit cause Leber congenital amaurosis; (c) biallelic mutations in PLA2G5, a gene encoding group V phospholipase A2, cause benign fleck retina. The consequences of mutations in these and other disease-related genes (RDH5, GRM6, KCNV2, OAT and SAG) on retinal structure (spectral domain optical coherence tomography, fundus autofluorescence imaging) and visual function (electrophysiology, perimetry testing) have been studied; features that may have mechanistic relevance have been identified. Additionally, DNA sequence variation of a highly polymorphic gene (C2ORF71), recently associated with photoreceptor degeneration, has been studied and quantified in patient and control samples. Basic bioinformatics tools to analyse genomic data have been developed (bash, perl, python and R programming languages). Overall, results presented in this thesis contribute to an understanding of Mendelian retinal disease that is not only observational but also mechanistic.
9
De, Vos Michel. "Genetic and epigenetic studies of autosomal recessive predisposition to neoplasia." Thesis, University of Leeds, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.485772.
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The availability of comprehensive genetic and structural data on the human genome, far from signalling the end of the era of human genetics, has greatly increased the power of genetic approaches to biological and pathological questions. For autosomal recessive . disorders, homozygosity mapping has proved to be a powerful method for gene mapping and identification. In this thesis, linkage and molecular studies are described of two distinct disorders offamilial cancer predisposition. .' Through homo,zygosity mapping of rare cases ofAsian origin, an attempt has been made to refine the localisation, on chromosome 19q13.4, of a gene causing biparental complete hydatidiform mole (BiCHM), a condition that predisposes to gestational trophoblastic disease and to choriocarcinoma. In one other family, that did not show linkage to the 19q13.4 locus, high-resolution mapping of an autozygous segment on chromosome 10 was p~rformed. Although BiCHM is geneti~ally heterogeneous, methylation studies of imprinted genes demonstrated an identical global lack of maternal imprints in the abnormal conceptions of all cases tested, which points towards a common oocyte-specific defect of epigenetic control underlying most if not all BiCHM cases. Using a similar approach, homozygosity ~apping ~as performed in an Asian family with an unusual combination of early-onset haematological and brain tumours, along with features suggestive of neurofibromatosis type I (NFl). Biallelic mutations in PMS2, a mismatch repair gene rarely implicated in HNPCC and Turcot syndrome, were eventually identified in seven unrelated families with this cancer syndrome. Evidence was obtained that the R802X nonsense mutation, which was subsequently found in 5 unrelated Pakistani Muslim fCl:milies, may represent a common allele in this population. This could have important implications for future carrier screening programs. Finally, a start was made in establishing the nature and the clinical significance ofgene conversion between PMS2 proper and PMS2CL, a novel inverted pseudogene, located less than I Mb centromeric ofPMS2.
10
Wood, Shaun Roger. "Development of AAV-mediated gene therapy for autosomal recessive bestrophinopathy." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:e0925bc0-8f36-4a76-9366-bc7dc316c5af.
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The bestrophinopathies are a set of inherited retinal degenerations caused by mutations in BEST1, and include Best vitelliform macular dystrophy (BVMD), autosomal dominant vitreoretinochoroidopathy (ADVIRC) and autosomal recessive bestrophinopathy (ARB). The corresponding protein, bestrophin-1, is localised to the basolateral membrane of the retinal pigment epithelium (RPE), where it is thought to function as a Ca<sup>2+</sup>-activated Cl- channel. Currently, there are no treatments for these conditions. In recent years, gene therapy has emerged as an exciting treatment option for inherited retinal disorders (IRDs). Gene delivery to retinal cells using a recombinant adeno-associated virus (rAAV) has produced positive results in several IRDs. Given the recessive nature of ARB, this thesis proposes that the rAAV-mediated delivery of bestrophin-1 to the RPE could represent a potential therapy. The aims of this thesis were to produce and compare rAAV vectors in vitro and in vivo for protein expression, localisation following transduction, restoration of chloride conductance in vitro and safety following sub-retinal injection in vivo. Following the production of two rAAV vectors expressing bestrophin-1, western blots confirmed bestrophin-1 protein expression following transduction of HEK293 cells in vitro. Immunocytochemistry (ICC) revealed bestrophin-1 expression that was localised to the cytosol. Whole-cell patch-clamping revealed a significant increase in chloride conductance in HEK293 cells transduced with AAV-BEST1 vectors which was then ablated upon the removal of chloride from the buffers. Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) indicated that the bestrophin-1 protein was successfully transcribed and translated from the BEST1 coding sequence (CDS). Sub-retinal injections of AAV-BEST1 produced bestrophin-1 expression in the RPE of wild-type C57BL/6 mice however significant retinal thinning was seen at higher doses of vector. In conclusion, rAAV-mediated transfer of bestrophin-1 to the RPE has potential to be a future therapy for ARB, however safety issues need to be addressed and an RPE-specific promoter could be more suitable.
11
Bruford, Elspeth A. "A genetic analysis of autosomal recessive forms of retinitis pigmentosa." Thesis, University of Edinburgh, 1997. http://hdl.handle.net/1842/21656.
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The aim of this project was to identify loci for recessive forms of RP by genetic linkage analysis, using patients with arRP and BBS, and to test for mutations in any resultant candidate genes. Pedigrees with arRP from south-central Sardinia, an ethnic outlier with a higher prevalence of recessive disease, were studied initially. Linkage analysis was carried out using genome-wide microsatellite markers, and genetic heterogeneity was identified among the 11 families studied. Examination of the data revealed potential linkage to D14S80, on chromosome 14q11, in a subset of families. Fine mapping with further markers in this region identified a region of homozygosity in one consanguineous family, suggesting identity-by-descent. A strong candidate gene for RP, neural retina specific leucine zipper (NRL), was found to be located with the region of homozygosity. NRL codes for an evolutionarily conserved protein which is expressed in all layers of the neural retina, and is thought to have a role in the transcriptional regulation of retinal genes, including rhodopsin. The NRL gene was studied in the consanguineous family by direct sequencing and mutation analysis, but no mutations were identified within the coding region. A total of 28 BBS pedigrees collected worldwide were studied using markers in regions where linkage was established during the course of the study. These loci are located on chromosomes 11q13, 16q21, 3p13-p12 and 15q22.3-q23. The results revealed significant genetic heterogeneity, with most families showing linkage to 11q13, and others being consistent with linkage to the 16q or 15q chromosomal regions. Some of the larger pedigrees could be assigned to specific loci, but many of the smaller families were too small for a definite assignment. The results of multipoint linkage analyses in these three linked chromosomal regions will help narrow down the region of search for candidate genes.
12
Hillermann, Renate. "Genetic and physical mapping studies of the Friereich's ataxia (FRDA) locus and mutational analysis of a novel candidate, STM7." Thesis, Imperial College London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264977.
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Bochukova, Elena G. "Expression of Wilson's disease genomic locus." Thesis, University of Oxford, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.275361.
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Chiu, Miliyun. "Galectin-3 and the development of autosomal recessive polycystic kidney disease." Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1445364/.
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Galectin-3 is a β-galactoside-binding lectin implicated in renal collecting duct development and differentiation. Autosomal recessive polycystic kidney disease (ARPKD) affects 1 in 20,000 humans, and is characterised by cyst development from collecting ducts. Galectin-3 retards cystogenesis in at least 2 in vitro models. Hence, I hypothesised that endogenous galectin-3 may reduce cyst formation in vivo, and investigated this in the congenital polycystic kidney mouse (cpk), a well-characterised ARPKD model. Widespread galectin-3 expression was detected in cpk cyst epithelia in a distinct distribution compared to other developmental markers and renal galectins, and also in other cystic mice and human PKD, raising the possibility that galectin-3 may be a common part of a 'cystogenic' pathway. Next, I investigated whether reduced galectin-3 accelerated cyst formation in vivo using cpk and galectin-3 mutants to generate double cpk/galectin-3 mutants. Initial results on a mixed genetic background demonstrated large variability, but still significantly increased cysts in mice lacking galectin-3. I then backcrossed onto a pure 129Sv background but offspring developed unexpected increased mortality and pancreatic cysts, which confounded this experiment. Hence, we imported different galectin-3 mutants to reassess on the C57BL/6j background: cyst formation was less rapid than mixed/129Sv, but significantly more cortical cysts were again observed in galectin-3 null mutants. I detected galectin-3 in the primary cilium and centrosomes both in vivo and in vitro in normal and cystic samples for the first time. At least some of the galectin-3 appears on the outside of the cilia and paclitaxel, a therapy that retards PKD in cpk mice, caused increased extracellular galectin-3, a location where the lectin might interact with cilia. Preliminary experiments were also performed to investigate ciliary function using atomic force microscopy. These data raise the possibility that galectin-3 may act as a 'natural' brake on cystogenesis in cpk mice, perhaps via ciliary roles.
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Eden, Emily Rose. "Investigation of a novel gene defect in patients with autosomal recessive hypercholesterolaemia." Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404425.
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Klein, Pontus. "Functions of GDNF/Ret signaling in models of autosomal recessive Parkinson’s disease." Diss., Ludwig-Maximilians-Universität München, 2011. http://nbn-resolving.de/urn:nbn:de:bvb:19-166901.
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Owen, Nicholas. "Molecular genetics of spinal muscular atrophy." Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342635.
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Bell, Rebecca Jane. "Genetics of x-linked and autosomal recessive hereditary nephropathy in the domestic dog." [College Station, Tex. : Texas A&M University, 2007. http://hdl.handle.net/1969.1/ETD-TAMU-2125.
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Alrayes, Nuha Mohammad. "Mutation analysis of autosomal recessive neurological disorders in consanguineous families from Saudi Arabia." Thesis, St George's, University of London, 2017. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.719148.
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The focus of this research project is the fundamentally important discovery of genetic mutations present in the Saudi Arabian population, concentrating mainly on offspring with neurological autosomal recessive disorders resulting from consanguineous marriages. The objective is to identify pathogenic gene variantsin known, novel, and potential candidate genes. In this research, microarrays were used for genome-wide homozygosity mapping to locate regions of homozygosity. This technique was followed with whole-exome sequencing to identify the causative gene located within the detected homozygous region, and the Sanger sequencing confirmed the mutations. Consanguineous families who presented at the paediatric or genetic clinics with two or more children having a neurological disorder were recruited, including the healthy parents, siblings, and other family members. Five candidate families have been recruited in this study. One family is a hereditary spastic paraplegia case with four affected children. Another family with two affected children of Perrault syndrome phenotype. Two more families who have children with microcephaly. In addition to three children of intellectual disability in one family. We have identified a DDHD2 truncating mutation in the first family and novel pathogenic variant of CLPP in the second family. In addition to AGMO gene alteration and previously reported stop-gain mutation in ASPM in the microcephaly families. Furthermore, the highlight of 5 candidate genes (ALKBH8, ANKK1, AMOTL1, TRAPPC6A and RSPH6CA) were found to be related to an intellectual disability phenotype. Further investigation by western blotting showed a difference in stability between normal and mutant proteins for both TRAPPC6A and AM0TL1. These are considered to be new findings for this intellectual disability phenotype.
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Jahns, (geb Issa) Lina [Verfasser]. "The role of CDK5RAP2 in autosomal recessive primary microcephaly (MCPH) / Lina Jahns (geb. Issa)." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2014. http://d-nb.info/1062949196/34.
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Bradshaw, Teisha Y. "The cellular phenotype of the neurodegenerative disease autosomal recessive spastic ataxia of Charlevoix-Saguenay." Thesis, Queen Mary, University of London, 2014. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8924.
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Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is an early onset neurodegenerative disorder resulting from mutations in the SACS gene that encodes the protein sacsin. Sacsin is a 520kDa multi-domain protein localised at the cytosolic face of the outer mitochondrial membrane with suggested roles in proteostasis and most recently in the regulation of mitochondrial morphology. An excessively interconnected mitochondrial network was observed as a consequence of reduced levels of sacsin protein following SACS knockdown in neuroblastoma cells as well as in an ARSACS patient carrying the common Quebec homozygous SACS mutation 8844delT. Moreover, it was suggested that sacsin has a role in mitochondrial fission as it was found to interact with mitochondrial fission protein Dynamin related protein 1 (Drp1). The aim of this thesis was to explore sacsin’s role in the regulation of mitochondrial morphology and dynamics in non-Quebec ARSACS patients and sacsin knockdown fibroblasts. This study shows that loss of sacsin function promotes a more interconnected mitochondrial network in non-Quebec ARSACS patients and in sacsin knockdown fibroblasts. Moreover, recruitment of the essential mitochondrial fission protein Drp1 to the mitochondria was significantly reduced in ARSACS patient cells and in sacsin knockdown fibroblasts. This reduced recruitment of Drp1 to mitochondria also occurred when cells were treated to induce mitochondrial fission. Furthermore, both the size and intensity of Drp1 foci localised to the mitochondria were significantly reduced in both sacsin knockdown and patient fibroblasts. Finally, reduced ATP production, decreased respiratory capacity of mitochondria and an increase in mitochondrial reactive oxygen species demonstrated impaired mitochondrial function in ARSACS patient and sacsin knockdown fibroblasts. These results suggest a role for sacsin in the stabilisation or recruitment of cytoplasmic Drp1 to prospective sites of mitochondrial fission similar to that observed by other mitochondrial fission accessory proteins.
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Sir, Joo-Hee. "Characterisation of the autosomal recessive primary microcephaly complex, CEP63-CEP152 in the vertebrate centrosome." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608038.
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Magwebu, Zandisiwe Emilia Z. E. "Molecular genetics: strategies to identify congenital cataract genes in captive-bred vervet monkeys." University of the Western Cape, 2013. http://hdl.handle.net/11394/4265.
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>Magister Scientiae - MSc<br>Molecular genetics: strategies to indentify congenital cataract genes in captive-bred Vervet
monkeys
Zandisiwe Emilia Magwebu
MSc thesis, Department of Medical Biosciences, University of the Western Cape
The present study describes molecular aspects of inherited congenital cataract in captive-bred
Vervet monkeys. Congenital cataracts are lens opacities that are present at birth or soon after
birth and include hereditary cataracts or cataracts caused by infectious agents. The MRC Primate
Unit is housing a colony of captive-bred Vervet monkeys in which 7.5% is suffering from
congenital cataract. However, the parents of the affected individuals were asymptomatic. Six
families within the colony have been identified to be affected by two types of morphologies (Ysutural
and total cataract). Based on the evidence provided above, it was speculated that the
colony was affected with autosomal recessive cataract.
The main aim of this study was to facilitate a strategy for managing breeding programs by
minimizing cataract occurrences in captive-bred Vervet monkeys. Integrated combination of
clinical, molecular and bioinformatic strategies were used to identify and assess reciprocal
candidate susceptibility genes for cataracts. The genes that are known to be responsible for most
human congenital cataract cases were prioritized. The genes include Heat shock transcription
factor 4 (HSF4), Crystalline Alpha A (CRYAA), glucosaminyl (N-acetyl) transferase 2 (GCNT2) and Lens intrinsic membrane protein 2 (LIM2). Twenty two subjects were selected based on their
morphology (5 carriers, 5 controls and 12 cataracts). 2ml of blood was collected for
Deoxyribonucleic acid (DNA) extraction. Coding exons and flanking regions were screened by
polymerase chain reaction (PCR) amplification and sequenced. The CLC DNA workbench was
used for results analysis.
The screening of four genes revealed 20 sequence variants which were not present in the control
individuals. Sequencing of HSF4 revealed three mutations: R116R, L245>L and P421>L in exon
5, 10 and 14, respectively. The coding exons for CRYAA showed two sequence variants: S134W
and K166N in exon 3. Twelve mutations were identified in exon one of all three GCNT2
transcripts (A, B and C). These mutations include: G212G, H256>H, M258>V, N275>N, V16>I,
Y122>F, S15>S, S24>N, S38>S, I118>I, D194>D and Y373>Y which was found in exon three
of all transcripts. There were no mutations in LIM2, however, three single nucleotide
polymorphisms (SNPs) were identified in exon 2 (P66>P) and 3 (I118>T and A127>T). The
above mutations were conserved when aligned with other species. The sequence variations vary
among the families and those individuals with the same or different cataract phenotype.
Based on these findings, it can be concluded that the four candidate genes harbour mutations that
are responsible for both phenotypes. The effect of these mutations in Vervet monkeys is not yet
understood, however, their impact will be further investigated. For future studies, it will be of
absolute importance to screen the entire family to verify that indeed cataract formation in this
colony is inherited in an autosomal recessive manner.
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O'Driscoll, C. A. "Autosomal recessive retinitis pigmentosa, identification and partial characterisation of a novel gene implicated in RP25." Thesis, University College London (University of London), 2010. http://discovery.ucl.ac.uk/19499/.
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The purpose of this project is to identify the causative gene for one type of autosomal recessive retinitis pigmentosa, RP25. Through CGH (comparative genome hybridisation) and mutation screening, independent mutations were identified in arRP affected Spanish families mapping to RP25. These mutations were identified within a cluster of uncharacterised gene transcripts all which have EGF-like repeat domains; Q5T669, Q5T1H1, Q9H557_human, Q5TEL3_human, Q5TEL4_human, Q5VVG4_human, and Q5T3C8. Through 5` and 3` RACE PCR analysis, the full length gene was revealed to incorporate the EGFL11 gene. On assembling all available data we noted that RP25 gene encompasses 30 exons belonging to nine previously predicted genes and 13 newly identified exons, totaling 43 exons and spanning the interval between 64,487,835 and 66,473,839 on chromosome 6q12. The RP25 full length gene transcript is retinal specific. The genomic length covers over 2.0 MB in size and is therefore the largest eye specific gene identified to date. It is also the fifth largest gene in the human genome to date. Homologs of the RP25 gene to Drosophila eys/eys-shut (Spacemaker) were identified, leading to the annotation of the name EYS (SPAM). An apparently intact eys gene is found across the mammalian clade, including monotremes (platypus) and marsupials (opossum). However, despite the mutations and the presumed loss of function associated with human disease, this gene has been dispensed with on at least four separate occasions in the last 100 million years of mammalian evolution including in the armadillo (Dasypus novemcinctus), little brown bat (Myotis lucifugus) and ruminant (cattle and sheep) lineages. EYS has acquired several (<3) reading-frame disruptions in three rodents (mouse, rat and guinea pig) representing two of the three major rodent clades. Through immunohistochemical and electron microscopy analysis, a signal for SPAM was identified in the outer segments of photoreceptor cells.
25
Moradi, P. "Leber Congenital Amaurosis and other autosomal recessive retinal dystrophies : a clinical and molecular genetic study." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1455735/.
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Leber congenital amaurosis (LCA) and the early onset retinal dystrophies (EORD) are a spectrum of autosomal recessively inherited genetic conditions affecting children who have visual impairment starting under the age of five years. There are currently 19 known genes that account for approximately two thirds of cases. Only two of these 19 genes (IMPDH 1 and CRX; not studied in this project) have been found to cause autosomal dominant LCA. This genetic heterogeneity makes the identification of these causative genes expensive and time consuming. Phenotype-genotype correlations are therefore important in directing efforts to determine the molecular cause of disease. The aims of this research project were to recruit and clinically characterise a large panel of LCA and EORD patients and to identify the underlying genetic cause of autosomal recessive disease. Patients were recruited from Moorfields Eye Hospital and Great Ormond Street Hospital. A full clinical examination was carried out. DNA samples were analysed using the Asper Ophthalmics LCA microarray chip and by direct sequencing. Large families, with several affected members, were examined using the Affymetrix gene chip arrays for regions of homozygosity and candidate gene sequencing was performed. DNA samples from 158 patients were obtained and 117 patients were examined clinically. A definitive molecular diagnosis was obtained for 26% of patients. Of the cohort of 158 patients with one or two mutated alleles identified and genotyped: RPE65 accounts for 1% of this cohort, 6% are due to mutations in CRB1, 15% are due to RDH12 mutations and 11% are due to mutations in CEP290. Two families were identified with novel CRALBP mutations. The genotype yield from the period of this research, August 2006- August 2008, is lower than that expected with newer technologies in 2014; such as next generation sequencing (NGS) or whole exome sequencing. Useful prognostic information gained will help future patients with these disorders. Patients with a molecular diagnosis may be eligible for clinical trials of gene replacement therapy.
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Ryan, Sean P. "Autosomal Recessive Polycystic Kidney Disease Epithelial Cell Model Reveals Multiple Basolateral EGF Receptor Sorting Pathways." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1274887553.
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Kruczek, P. M. "Characterisation of interacting partner(s) for EYS, a major gene implicated in autosomal recessive retinitis pigmentosa." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1473377/.
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Mutations in EYS are a common cause of autosomal recessive retinitis pigmentosa (arRP). EYS is one of the largest genes expressed in the retina and the role of the protein it encodes is presently unclear. It has been shown, however, that EYS localises to the outer segments of porcine photoreceptors and that the Drosophila orthologue of EYS is essential in the biogenesis of the ommatidium, where it interacts with prominin, a highly conserved protein implicated in retinopathies. The aim of this project was to examine the role of EYS in the retina by investigating its subcellular localisation and by identifying its interacting partners. Characterisation of the genetic structure of EYS has revealed that it has at least four isoforms expressed in the retina and testis. Immunocytochemistry studies have shown that EYS isoforms predominantly localise to the cytoplasm of cultured cells whereas immunohistochemistry studies in the primate retina have revealed that it localises to the photoreceptor ciliary axoneme. Yeast 2-hybrid screening has resulted in identification of one potential interacting partner of EYS, AIPL1, which is a molecular chaperone required for the proteostasis of the retina. Further analysis by co-immunoprecipitation and immunofluorescence has confirmed that AIPL1 interacts with the N terminal fragment of EYS isoforms 1 and 4 as well as EYS isoforms 2 and 3. Furthermore, co-immunoprecpietation assays and immunofluorescence studies have suggested that the human orthologues of EYS and Prominin-1 do not interact. The mutation screening of PROM1 has resulted in identification of seven heterozygous novel variants in six unrelated arRP patients; however, pathogenicity of the changes could not be established. Altogether, the results of the study have demonstrated that EYS may be a novel protein associated with the photoreceptor ciliary axoneme, where it could play a role in maintenance of the photoreceptor outer segments. Furthermore, the analysis of the interacome of EYS has demonstrated that it may require the activity of AIPL1 for correct folding and trafficking, and that the functional link of EYS and Prominin-1 described in Drosophila is unlikely to be conserved in humans. The knowledge gained from the study presented herein has brought us closer to unravelling the molecular mechanisms underlying arRP and adds to the overall understanding of the physiology of the retina in health and disease.
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Klein, Pontus [Verfasser], and Rüdiger [Akademischer Betreuer] Klein. "Functions of GDNF/Ret signaling in models of autosomal recessive Parkinson’s disease / Pontus Klein. Betreuer: Rüdiger Klein." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2011. http://d-nb.info/1048014614/34.
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Püttmann, Lucia [Verfasser]. "Identification and characterization of gene defects underlying autosomal recessive intellectual disability in two Iranian families / Lucia Püttmann." Berlin : Freie Universität Berlin, 2013. http://d-nb.info/1042441308/34.
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Pogue, Robert. "Genetic analysis as part of an integrated strategy for diagnosis in autosomal recessive limb-girdle muscular dystrophy." Thesis, University of Newcastle Upon Tyne, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299052.
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Abera, Aron. "The molecular and cellular defect underlying autosomal recessive hypercholesterolemia (ARH) in the first kindred identified in South Africa." Master's thesis, University of Cape Town, 2005. http://hdl.handle.net/11427/3502.
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Includes bibliographical references (leaves 82-88).<br>Monogenic defects in the low density lipoprotein (LDL) uptake pathway occur commonly in South Africans, particularly in the Afrikaner community where inheritance is typically autosomal dominant, arising predominantly from abnormal structure and thus function of the LDL receptor (LDLr). Defects in LDLr binding domain of apolipopreteinB-100 (apoB-100) are rarely encountered and are know as Familial defective apoB-100 (FDB). Several critical proteins are active in the LDL uptake pathway and their deficiencies are now being shown to underlie the rare autosomal recessive forms of hypercholesterolemia (ARH). One of these proteins is the LDLr adaptor protein know as ARH, which is presumed to facilitate interaction of the cytoplasmic tail of the LDLr with the internal protein matrix required for the receptor internalisation.
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BEDINI, GLORIA. "Shwachman-Diamond Syndrome: an autosomal recessive inherited bone marrow failure disorder with defective angiogenesis and lymphoid lineage impairment." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2021. http://hdl.handle.net/10281/304798.
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La sindrome Shawachman-Diamond (SDS) è una malattia multi-organo caratterizzata da disfunzioni midollari ed insufficienza pancreatica. I pazienti SDS sono inoltre soggetti a sviluppo di anomalie ematologiche gravi, quali neutropenia, SMD e/o LMA. Nella prima parte di questo lavoro ci siano focalizzati sullo studio dell’alterata capacità angiogenica in vitro delle MSCs derivate da pazienti SDS. L’angiogenesi non coinvolge solo la patogenesi dei tumori solidi, ma anche lo sviluppo delle malattie ematologiche. Le MSCs sono in grado di supportare l’angiogenesi attraverso il differenziamento cellulare, l’interazione cellula-cellula e mediante meccanismi autocrini o paracrini. Grazie a modelli in vivo ed in vitro, il nostro gruppo di ricerca ha recentemente dimostrato come le SDS-MSCs siano caratterizzate da un alterato potenziale angiogenico. Qui, abbiamo confermato l’anomala capacità angiogenica in vitro delle cellule mesenchimali SDS dopo stimolazione angiogenica. Abbiamo dimostrato come questa alterazione sia associata a cambiamenti nel pathway di segnalazione TGFβ1/VEGFA. Infatti, l’espressione di diversi fattori di crescita in grado di stimolare il rilascio endogeno di VEGFA ed in grado di essere indotti da TGFβ1 è down-regolata nelle SDS- vs HD-MSCs. Inoltre, la somministrazione esogena di TGFβ1 o VEGFA permette la reversione del fenotipo angiogenico solo nelle cellule mesenchimali derivanti dai pazienti gravemente neutropenici. In fine, abbiamo dimostrano che a seguito di stimolo angiogenico i livelli proteici di P53 sono raddoppiati nelle SDS-MSCs vs HD-MSCs, analogamente al numero di cellule in apoptosi precoce e tardiva. Complessivamente, i nostri dati indicano un forte collegamento tra TGFβ1 e VEGFA nella modulazione dell’alterata capacità in vitro delle SDS-MSCs. Inoltre, forniscono un razionale per futuri studi mirati alla comprensione della correlazione tra angiogenesi e grado di neutropenia dei pazienti. Una migliore comprensione dei meccanismi molecolari alla base della regolazione del numero e della funzionalità dei neutrofili potrebbe portare a nuove strategie terapeutiche atte alla gestione delle infezioni ricorrenti dei pazienti SDS. La seconda parte del lavoro, invece, si è focalizzata sull’analisi dei meccanismi molecolari e dei pathways di segnalazione responsabili della neutropenia e dell’evoluzione SMD o LMA dei pazienti SDS. STAT3 è un regolatore di diversi processi cellulari, quali granulogenesi dei neutrofili, leucemia e trasformazione maligna del linfoma. Inizialmente riconosciuto come un fattore di trascrizione attivato da IL6, oggi è anche considerato un substrato diretto di mTOR. Recentemente, è stato dimostrato che mTOR e STAT3 sono costitutivamente up-regolati in leucociti primari e linee cellulari linfoblastoidi derivati da pazienti SDS. In questo lavoro, dimostriamo che la via di segnalazione mTOR-STAT3 è up-regolata anche in altre tipologie cellulari appartenenti alla linea linfoide dei pazienti SDS. Inoltre, i nostri dati rivelano elevati livelli di IL6 sia in surnatanti cellulari derivanti da linfoblasti, cellule mononucleate di midollo osseo e mesenchimali, sia in campioni di plasma ottenuti da una coorte di 10 pazienti SDS. Da notare che, l’inibizione di mTOR mediata da everolimus riporta a livelli basali la fosforilazione di STAT3. In ultimo, l’inibizione di mTOR-STAT3 porta alla normalizzazione dei livelli di espressione di IL6. Complessivamente, i nostri dati rafforzano l’ipotesi che la sindrome SDS interessa sia il compartimento linfoide che mieloide e suggerisce everolimus come potenziale agente terapeutico per ridurre l’eccessiva attivazione del pathway mTOR-STAT3 [Vella A., et al. 2020]. La scoperta di nuove alterazioni nei pathway molecolari che regolano la sindrome SDS potrebbe permettere l’individuazione di target terapeutici mirati al miglioramento delle alterazioni ematologiche ed all’evoluzione leucemica di questi pazienti.<br>Shwachman-Diamond Syndrome (SDS, OMIM 260400) is a multi-organ disorder mainly characterized by bone marrow (BM) dysfunctions and exocrine pancreatic insufficiency. SDS patients present also severe haematologic abnormalities, with neutropenia as the most common deficiency. Of note, SDS patients have an increased risk for myelodysplastic syndrome (MDS) and malignant transformation to acute myeloid leukaemia (AML).
In the first part of this work, we focused our attention on the in vitro angiogenic capability of SDS-mesenchymal stromal cells (MSCs). Angiogenesis is not only involved in the pathogenesis of solid tumours, but also in haematological malignancies. MSCs can potentiate angiogenesis via direct cell differentiation, cell-cell interaction, and autocrine or paracrine effects. Using both in vitro and in vivo models, our research group recently demonstrated that SDS-MSCs display a marked impairment in their angiogenic potential. Here, we confirm that SDS-derived cells obtained from a cohort of 10 patients show altered angiogenic properties in response to angiogenic stimuli and that the defective in vitro tube formation is associated with TGFβ1/VEGFA signalling abnormalities. Indeed, we show that the expression of several growth factors able to increase the endogenous release of VEGFA and to be induced by TGFβ1 is down-regulated in SDS- vs HD-MSCs. Moreover, by providing the exogenous administration of VEGFA or TGFβ1, we demonstrate that only SDS-MSCs from severely neutropenic patients can restore their angiogenic properties. Finally, our data also show that under angiogenic stimulation, P53 protein levels are 2-fold increase in SDS- vs HD-MSCs, as well as the number of early/late apoptotic cells. Collectively, our results suggest a strong link between TGFβ1 and VEGFA in dictating the altered in vitro angiogenic capability of SDS-MSCs. Moreover, we provide a rational to investigate whether the defective angiogenesis driven by SDS-MSCs could be related to neutropenia. The better comprehension of the molecular mechanisms regulating neutrophil number and functionality may lead to novel strategies for the management of recurrent SDS infections.
The second part of our study was focused on the analysis of the molecular mechanisms and signalling pathways responsible of SDS patients neutropenia, and evolution to MDS or AML. Signal transducer and activator of transcription 3 (STAT3) is a key regulator of several cellular processes including neutrophil granulogenesis, leukaemia, and lymphoma malignant transformation. Firstly recognised as an interleukin-6 (IL6)-activated transcription factor, nowadays STAT3 is also considered a direct substrate for the mammalian target of rapamycin (mTOR). Recently, it has been demonstrated that both mTOR and STAT3 pathways are constitutively up-regulated in primary leukocytes and lymphoblastoid cell lines derived from SDS patients. Here, we show that mTOR-STAT3 signalling is markedly up-regulated in several cell subsets belonging to the lymphoid compartment of SDS patients. Furthermore, our data reveal elevated IL6 levels in cellular supernatants obtained from lymphoblasts, bone marrow mononuclear and mesenchymal stromal cells, and plasma samples obtained from a cohort of 10 patients. Of note, everolimus-mediated inhibition of mTOR signalling was associated with the basal state of phosphorylated STAT3. Finally, inhibition of mTOR-STAT3 pathway leads to normalization of IL6 expression in SDS cells. Altogether, our data strengthen the hypothesis that SDS affects both lymphoid and myeloid blood compartment and suggest everolimus as a potential therapeutic agent to reduce excessive mTOR-STAT3 activation in SDS [Vella A., et al. 2020].
The discovery of new altered molecular pathways underlying SDS pathophysiology could lead to the identification of new therapeutic targets for the correction of SDS-related haematological defects and the prevention of leukemic evolution.
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Duncan, Emma Jane. "The neurodegenerative disease Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) : cellular defects due to loss of sacsin function." Thesis, Queen Mary, University of London, 2016. http://qmro.qmul.ac.uk/xmlui/handle/123456789/23110.
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Sacsin, which is mutated in the neurodegenerative disease Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS), is a 520 kDa modular protein with regions of homology to molecular chaperones and domains linking to the ubiquitin proteasome system. This suggests a role in proteostasis. Previously, sacsin has been shown to partially localise with mitochondria, and loss of sacsin results in elongated and dysfunctional mitochondria. Moreover, alterations in neurofilaments have recently been reported in a mouse model of ARSACS. Despite these findings, pathophysiological mechanisms of ARSACS are poorly understood. The aim of this thesis was to elucidate the cellular role of sacsin by determining how loss of its function leads to the observed mitochondrial and intermediate filament defects. This hoped to shed light on the mechanism of disease in ARSACS. The results indicate that the mitochondrial elongation seen in ARSACS is likely due to reduced mitochondrial localisation of the essential fission factor DRP1. This may be mediated by loss of function of a complex involving sacsin and dynactin-6, a subunit of the dynein-dynactin motor complex, which has previously been shown to be required for DRP1 mitochondrial recruitment. DRP1-mediated mitochondrial fission is necessary for mitochondrial quality control; hence a disruption to mitochondrial quality control is likely to occur in sacsin deficient cells, which may explain the mitochondrial dysfunction in ARSACS. Furthermore, sacsin null cells display a dramatic collapse and perinuclear bundling of the vimentin intermediate filament network. This is coupled with the displacement of cellular organelles, particularly mitochondria, early endosomes and the Golgi, which accumulate at the periphery of the vimentin bundle. These are characteristic features of aggresome formation, indicating an aggregation of misfolded protein, which occurs due to disrupted proteostasis. Further supporting this, the proteostasis components ubiquitin, HSP70, LAMP2 and p62 are recruited to the perinuclear vimentin bundles. In summary, the findings of this thesis indicate a role for sacsin in mitochondrial and protein quality control, the dysfunction of which is likely to be particularly detrimental in neurons. Mitochondrial dysfunction along with protein misfolding and aggregation are implicated in many neurodegenerative diseases, and ARSACS is no exception.
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Olteanu, Dragos S. "Dysregulated ENAC and NHE function in cilium-deficient renal collecting duct cell monolayers a model of polycystic kidney disease /." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2007. https://www.mhsl.uab.edu/dt/2009r/olteanu.pdf.
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Moheb, Lia Abbasi [Verfasser]. "Identification of three novel genes for autosomal recessive intellectual disability and molecular characterization of the causative defects / Lia Abbasi Moheb." Berlin : Freie Universität Berlin, 2012. http://d-nb.info/1026883849/34.
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Ropers, Fabienne [Verfasser]. "Identification of a novel candidate gene for non-syndromic autosomal recessive intellectual disability : the WASH complex member SWIP / Fabienne Ropers." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2012. http://d-nb.info/1028496133/34.
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Almeida, Lorena Schneider. "Análise molecular do gene CRTAP através da técnica de PCR-SSCP-sequenciamento em pacientes com osteogênese imperfeita do Espírito Santo." Universidade Federal do Espírito Santo, 2013. http://repositorio.ufes.br/handle/10/5746.
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Previous issue date: 2013-02-28<br>The Osteogenesis Imperfecta (OI) is a genetic disease characterized by structural defects of type I collagen protein or by reducing its biosynthesis causing decreased bone mass and predisposition to fractures and bone deformities. Approximately 90% of individuals with OI exhibit autosomal dominant inheritance caused by mutations in the genes COL1A1 and COL1A2. However, the number of genes linked to autosomal recessive forms of OI is increasing in the literature. The CRTAP gene was the second identified causing recessive inheritance OI. This gene has 6622 bp, seven exons and encodes a protein of 46.5 kDa. The CRTAP encoding the protein cartilage associated (CRTAP) which is part of the collagen 3-hydroxylation complex, responsible for post-translational modifications during the biosynthesis of collagen
molecule. CRTAP mutations are related to severe and lethal form of the disease. The target of this research was evaluating the exons of CRTAP and its adjacent regions
in OI patients from Espírito Santo thought the Single-Stranded Conformation Polymorphism (SSCP) screening of mutations and sequencing. We studied 24 patients with clinical diagnosis of OI from Hospital Infantil Nossa Senhora da Glória de Vitória, Brazil. The patients/ ages ranged from 2 to 16 years (median: 14.5). The sex proportion of the patients was 15 males and 9 females. Eleven patients have mild clinical symptoms of the disease, 5 show moderate symptoms and 9 were severe
cases. The lethal OI cases were not obtained by methodological difficulties. We found the polymorphisms c.534C> T previously reported in exon 2 of the CRTAP gene in
patients from sample. No pathogenic mutations were found in this study. The results of this study suggest that mutations in CRTAP are rare in ES population. These data may assist in developing more efficient methodological strategies for molecular diagnosis of OI<br>A Osteogênese Imperfeita (OI) é uma doença genética caracterizada por defeitos estruturais da proteína do colágeno tipo I ou por redução da sua biossíntese causando diminuição da massa óssea e a predisposição a fraturas e deformidades
ósseas. Aproximadamente 90% dos indivíduos com OI apresentam herança autossômica dominante causada por mutações nos genes COL1A1 ou COL1A2. Contudo, é crescente o número de genes ligados à herança autossômica recessiva da OI descritos na literatura. O gene CRTAP foi o segundo gene identificado causando OI com herança recessiva. Este gene possui 6.622 pb, 7 exons e codifica
uma proteína de 46,5 KDa. O gene CRTAP codifica a proteína da cartilagem associada (CRTAP) que faz parte do complexo prolil 3-hidroxilação, responsável por modificações pós-traducionais fundamentais durante a biossíntese da molécula de colágeno. Mutações no gene CRTAP estão relacionadas à forma grave ou letal da doença. Esta pesquisa teve como objetivo avaliar as porções codificantes do gene CRTAP e suas regiões adjacentes em pacientes com OI do estado do Espírito Santo por meio da técnica de triagem de mutações de Polimorfismo Conformacional de Fita Simples (SSCP) e sequenciamento. Foram estudados 24 pacientes com diagnóstico clínico de OI do Hospital Infantil Nossa Senhora da Glória de Vitória, Brasil. As idades dos pacientes variaram de 2 a 16 anos (mediana: 14,5 anos) sendo 15 indivíduos do sexo masculino e 9 do sexo feminino, 11 pacientes apresentam a
forma leve da doença, 5 a forma moderada e 9 a forma grave da doença. Os casos letais de OI não foram obtidos por dificuldades metodológicas. Foi encontrado o polimorfismos c.534C>T no exon 2 do gene CRTAP, previamente relatado na
literatura, em pacientes da amostra. Não foram identificadas mutações patogênicas neste estudo. Os resultados desse trabalho sugerem que mutações no gene CRTAP são raras na população com OI do ES, corroborando dados da literatura. Esses dados poderão auxiliar na elaboração de estratégias metodológicas mais eficientes para o diagnóstico molecular de OI
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Majava, M. (Marja). "Molecular genetics of Stickler and Marshall syndromes, and the role of collagen II and other candidate proteins in high myopia and impaired hearing." Doctoral thesis, University of Oulu, 2007. http://urn.fi/urn:isbn:9789514283628.
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Abstract
Stickler and Marshall syndromes are genetic disorders both inherited in an autosomal dominant manner. The genotype-phenotype correlation was performed in ten Stickler/Marshall syndrome patients with mutations in the COL11A1 gene. Four patients had a phenotype classified as Marshall syndrome based on early-onset severe hearing loss and characteristic facial dysmorphism. A splice site mutation in intron 50 of COL11A1 was found in these patients, while the remaining six patients had an overlapping Marshall-Stickler phenotype with a mutation elsewhere in the gene. These results indicate exon 50 as a hot spot for splice site mutations leading to a phenotype of Marshall syndrome rather than Stickler syndrome.
Collagen II (COL2A1) precursor mRNA undergoes alternative splicing resulting in two different isoforms, IIA including exon 2 and IIB excluding exon 2. Recent evidence indicates that premature termination codon mutations in exon 2 cause Stickler syndrome with no or minimal extraocular manifestations.
Two mutations were observed in this study: Cys64Stop, and a novel structural mutation, Cys57Tyr. Results from the COL2A1 mini-gene studies suggested that both mutations altered positive cis elements for splicing resulting in a lower IIA:IIB ratio. The results further emphasize the importance of exon 2 in the development and normal function of the eye. In addition, patients displaying eye phenotypes in the absence of extraocular manifestations should be analyzed first for exon 2 mutations.
Linkage analysis identified a new locus for autosomal recessive nonsyndromic hearing loss (DFNB32) on chromosome 1p13.3-22.1 in a Tunisian family with congenital profound autosomal recessive deafness. The COL11A1 gene is located in this region and was analyzed as a candidate gene. No disease causing sequence variation was observed.
The analysis of 85 English and 40 Finnish subjects with high myopia resulted in the identification 23 sequence variations in the SLRP genes LUM, FMOD, PRELP, and OPTC. The two intronic variations and seven amino acid changes, one synonymous and six non-synonymous, were not found in the 308 controls analyzed. Five changes were detected in opticin, and all but one were shown to co-segregate with high myopia in families with incomplete penetrance. The results suggested that sequence variations in the SLRP genes expressed in the eye are genetic risk factors underlying the pathogenesis of high myopia.
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Okoye, Chukwuebuka D., and Ayodeji Segun Bamisile. "Peculiarities of sickle cell anemia in patients with malaria in Africa." Thesis, Sumy State University, 2016. http://essuir.sumdu.edu.ua/handle/123456789/47876.
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Background. Sickle cell anemia is an autosomal recessive disease caused by a single point mutation in nucleobase sequence of chromosome 11 with substitution of glutamic acid by valine and formation of HbS is widespread in mainly African countries with prevalence of 20% - 30% in Cameroon, Republic of Congo, Gabon, Ghana, Nigeria and 45% in Uganda. Malaria on the other hand is an infection caused by a parasite (Plasmodium sp.) that is transmitted to humans by female anopheles mosquito and is prevalent in tropical and subtropical regions of Africa due to increased rainfall, constant high temperatures and high humidity.
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Ghani-Kakhki, Mahdi [Verfasser]. "Molecular genetic and cytogenetic analyses of autosomal recessive primary microcephaly (MCPH) : mouse model, new locus and novel mutations / Mahdi Ghani-Kakhki." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2013. http://d-nb.info/1031099646/34.
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Tawamie, Hasan [Verfasser], André [Akademischer Betreuer] Reis, and Falk [Gutachter] Nimmerjahn. "Identification and characterization of candidate genes in individuals with autosomal recessive intellectual disability / Hasan Tawamie ; Gutachter: Falk Nimmerjahn ; Betreuer: André Reis." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2018. http://d-nb.info/1161184287/34.
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Lebeko, Kamogelo. "Genetic aetiology of autosomal recessive non-syndromic hearing loss in sub-Saharan African patients: evaluation using targeted and whole exome sequencing." Doctoral thesis, Faculty of Health Sciences, 2019. http://hdl.handle.net/11427/30376.
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Hearing Loss (HL) is one of the highest contributors to disability worldwide. The highest incidence of the disease is seen in developing countries, such as those in subSaharan Africa (SSA). Patients affected with disabling HL are reported to be more than 466 million worldwide. The causes of HL can either be environmental or genetic with each contributing about 50% towards all cases, in many settings. In developing countries, the environment might contribute more due to poor health services and infrastructure available to the population. In the absence of environmental causes, there is a genetic component at play, that is largely unknown in African populations. Up to 70% of HL of genetic origin are non-syndromic (NS). The mode of inheritance is recessive in nearly 77% of non-syndromic HL. Up to date, more than 100 genes have been associated with HL harbouring more than 1000 causative variants. In many populations of European and Asian descent, pathogenic variants in GJB2 (connexin gene 26) and GJB6 (connexin gene 30) are a major contributor to autosomal recessive non-syndromic hearing loss (ARNSHL). Comprehensive hearing health care programs should cover genetic causes by providing molecular testing, and genetic counselling, specifically SSA where genes and mutations causing HL remain largely unknown. The aim of this project was thus to uncover the genetic causes of HL among patients’ cohorts from Cameroon and South Africa. This was addressed by 1) sequencing common variants in the most relevant genes in other populations (GJB2 and GJB6), 2) using a targeted gene panel to resolve HL in 10 multiplex families from Cameroon presenting with ARNSHL and negative for GJB2 and GJB6 mutations screening, 3) screening novel variants found in known genes in a cohort of 82 singleplex HL cases from Cameroon and South Africa, and lastly, 4) using Whole Exome sequencing to explore the two unresolved multiplex cases with and subsequent findings confirmed by functional studies, and also screened in 80 singleplex HL cases. The following findings are reported: GJB6, GJA1 mutations screening and literature review No GJA1 or GJB6 mutation was not found in multiplex and simplex cases of HL in both Cameroonians and South Africans. The review of the literature confirms that the prevalence of GJB2- or GJB6-related NSHL is approximating to zero in most subSaharan African populations. Targeted Exome Sequencing (OtoSCOPE) The targeted genes, panel that included 116 genes, was able to resolve 7 of 9 families (77.8%) which were successfully sequenced, with one family failing to be sequenced. The causative variants identified in the 7 resolved families were : 1) compound heterozygous c.5806_5808delCTC and c.5880_5882delCTT in MYO7A; 2) compound heterozygous c.646T>A (p.Phe216Ile) and c.38G>A (p.Arg13His) in LOXHD1; 3) homozygous c.766-2A>G in OTOF; 4) a deletion and a complex copy number variation in STRC; 5) compound heterozygous c.1678G>A (p.Asp560Asn) and c.2007C>A(p.Asp669Glu) in SLC26A4; 6) Homozygous c.1996C>T(p.Arg666Stop) in MYO7A; 7) compound heterozygous c.6399C>A(p.Asp2133Glu) and c.2000T>C (p.Met667Thr) in CDH23. Five out of 12 variants were novel. Screening of these causative variants in known genes, in 82 singleplex HL cases from Cameroon and South Africa was unable to resolve any of the cases: the variants were in either heterozygous in low frequency or absent. Bioinformatic pathways exploration of SNP data of known HL genes revealed an extensive network within the HL genes, with 10 identified as important nodes, including MYO7A. Most HL genes were found to be involved in two biological processes which were sensory perception of mechanical stimulus (GO: 0050954, p= 1.430e-8) and sound (GO: 0007605, p = 1.246e-8). The molecular functions of variants found within these genes were found to mostly fall within the binding (GO: 0005488) and/or structural molecule activity (GO: 0005198). Whole Exome sequencing Whole exome sequencing was performed on four of the nine multiplex families: the two families that were unresolved by targeted panel sequencing, and two previously resolved families that were used as positive controls for the variant annotation and filtering pipeline. The results were the resolution of 3/4 families, including the two- positive control. The previously unresolved “family 8” was found to harbour a novel variant within the GRXCR2 gene, a gene only associated with HL once before. The c.251delC variant was revealed through in silico studies to cause a premature stop codon at position 116 due to its frameshift effect. The screening of this variant in our cohort of 80 singleplex cases revealed one other unrelated HL patient harbouring this causative variant. Due to the limited literature on the gene and its protein, in silico studies were used to show the predicted secondary structure folding of the protein as well as potential protein binding regions. Analysis showed that the predicted loss of a stable region of the protein as well as that of a putative binding domain could explain the pathogenic nature of the variant. In vitro studies showed that the variant hindered the detection of the protein by way of a DDK tag downstream in the plasmid. Additionally, GFP-Tagged GRXCR2 showed altered expression pattern in the variant when compared to the wildtype. In summary, our data has revealed the efficacy of using next generation sequencing tools in resolving HL among sub-Saharan African patients as opposed to the single candidate gene approach. In our quest, we have employed two widely used strategies, targeted panel and whole exome sequencing (WES), both of which have had great successes in various populations. The targeted approach was able to resolve 77.8% of our families but did not detect variants for two of the families revealing the presence of other variants harboured in rarely associated gene not captured or included on the panel. This prompted for the use of a more comprehensive approach such as WES. These results corroborated with those of two families previously resolved by targeted exome sequencing. Additionally, one of the previously unresolved family was now resolved. This showed that WES was sensitive enough to detect variants in known HL genes but comprehensive enough to detect variants in other regions of the exome which have not been associated with HL or rarely associated with HL. The benefit of WES also extends to the contribution of exomic data from patients of African descent as there is an underrepresentation of this group in exome repositories as well as genomic or SNP databases. To the best of our knowledge, this is the first study to use WES to resolve HL in patients of African descent. The other benefit of such a venture is the use of this data not only for patients in SSA but also those in the diaspora. In conclusion, we have successfully demonstrated the feasibility of using NGS tools in identifying causative variants in HL patients in SSA. Additionally, we have shown that WES is a more suitable approach to trying to resolve HL in Africa. Therefore, the data strongly support that genetic studies on families segregating HL in SSA could be the next frontier of HL genetic research, of global importance through discovering novel variants in known genes, and potentially novel genes. These studies will improve HL genetic diagnosis, retrospective counselling and testing, prevention and care including future prediction of treatment outcomes in sub-Saharan Africans, and in people of African descent.
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Elbaghir, Omer Elsayed Liena. "Hereditary spastic paraplegias : clinical spectrum in Sudan, further deciphering of the molecular bases of autosomal recessive forms and new genes emerging." Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066056/document.
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Les paraplégies spastiques héréditaires (PSH) font partie d’un groupe plus large de pathologies neurodégénératives associant une spasticité. J’ai exploré la variabilité clinique et moléculaire de ces pathologies à l’aide d’une cohorte de familles soudanaises. Nous avons recruté 41 familles soudanaises [337 individus/106 atteints de PSH]. J’ai extrait l’ADN génomique et constitué une banque. Le criblage de gènes candidats a été réalisé dans 4 familles en fonction du phénotype des patients. La technologie de séquençage de nouvelle génération (SNG) appliquée à 74 gènes de PSH a ensuite été appliquée aux 37 cas restants. Enfin, le séquençage de l’exome a permis de rechercher les gènes en cause dans les cas négatifs. Dans certains cas, des études fonctionnelles ont été utilisées afin de valider l’effet biologique des mutations. J’ai pu identifier la cause génétique dans 17 familles. Dans 12 familles, la mutation concernait un gène de PSH connu. Dans 3 familles, un nouveau gène a été identifié. 5 gènes candidats restent à départager dans 2 familles. Il est à noter que parfois, de multiple mutations ou maladies génétiques ségrégaient dans nos familles, dans la même branche ou dans des branches séparées. La complexité de ces familles fortement consanguines a rendu l’analyse des données du SNG difficile. Une autre particularité a été l’hétérogénéité clinique associée à des mutations du même gène entre patients de la même famille ou en comparaison avec la littérature. Ce travail est la première étude à grande échelle de patients soudanais avec PSH et rapporte de nouveaux gènes en cause, prérequis pour mieux comprendre dans le futur les mécanismes sous-jacents<br>Hereditary spastic paraplegias (HSP), a heterogeneous group of spastic neurodegenerative disorders which impose diagnostic challenges. I explored the clinical varieties and genetic pathways of spastic neurodegeneration in a familial Sudanese cohort. We recruited 41 Sudanese families [337 individuals/106 HSP patients]. I have established a genomic DNA bank and when necessary, skin biopsies and fibroblasts were also obtained. A phenotype-based candidate gene approach was followed in 4 families. A targeted next generation sequencing (NGS) for 74 HSP-related genes was the main screening strategy in all-remaining 37 families. Whole exome sequencing (WES) was done in search for novel mutations in new genes in families with negative screening results. Occasionally, functional studies were conducted when feasible and relevant. I identified the genetic cause in 17/41 families. In 12 families, the mutated genes were known HSP genes. In 3 families, novel genes were identified mutated. 5 candidate genes segregated with disease in 2 other families with more experiments needed to conclude. Analysis of the NGS screening panel and of WES data imposed certain challenges as multiple genetic disorders were sometimes found running in parallel in the same/different branches of highly inbred families. We could expand the phenotypic heterogeneity of these disorders due to clinical differences observed between Sudanese patients and patients of other origins even when caused by mutations by the same gene/variant. This is the first genetic screening in a large set of HSP families in Sudan. It describes new causative genes, paving the way for further deciphering of the underlying mechanisms
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Hussain, Muhammad Sajid [Verfasser], Peter [Akademischer Betreuer] Nürnberg, Angelika Anna [Akademischer Betreuer] Noegel, and Guenter [Akademischer Betreuer] Schwarz. "Molecular Genetic Analysis of Autosomal Recessive Primary Microcephaly in Pakistani Kindreds / Muhammad Sajid Hussain. Gutachter: Peter Nürnberg ; Angelika Anna Noegel ; Guenter Schwarz." Köln : Universitäts- und Stadtbibliothek Köln, 2011. http://d-nb.info/1038267080/34.
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Hauck, Fabian. "Primary T cell immunodeficiencies associated with disturbed proximal T cell receptor signalling caused by human autosomal recessive LCK, ZAP-70 and ITK-mutations." Phd thesis, Université René Descartes - Paris V, 2013. http://tel.archives-ouvertes.fr/tel-00914375.
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T lymphocytes express either a preTCR, or a clonotyoic γδ TCR or αβ TCR together with the CD3-complex and the associated ζ-chain. TCR:CD3:ζ-signalling is crucial for T cell development and antigen-specific activation including proliferation, differentiation, effector functions and apoptosis of mature T cells. Protein tyrosine kinase (PTK) cascades lie at the heart of proximal TCR:CD3:ζ-signalling. The CSK-, SRC-, SYK- and TEC-family members C-terminal SRC kinase (CSK), lymphocyte-specific protein tyrosine kinase (LCK), ζ-chain associated protein tyrosine kinase of 70 kDa (ZAP-70) and interleukin-2-inducible T cell kinase (ITK), respectively, are the major T cell players. After TCR:CD3:ζ-complex triggering, activation of PTKs result in tyrosine phosphorylation signals. These include phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) of the CD3 and ζ-chains, adaptor proteins that nucleate the proximal LAT:SLP-76-signalosome controlling almost all TCR:CD3:ζ-induced signalling events. These events initiate Ca2+-flux, activation of mitogen-activated protein kinases (MAPKs), activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB), activation of nuclear factor of activated T cells (NFAT) and activator protein 1 (AP-1) as well as actin reorganization, cell-adhesion and motility.Througout the last five decades, the immune system has been extensively investigated in vitro and in animal models such as the murine system. Additionally, studying and taking care of human primary immunodeficiency diseases (PIDs) has been seminal for our understanding of the human immune system as animal models not always recapitulates the subtleties found in men.In my doctoral thesis I report the first case of autosomal recessive human LCK-deficiency, a novel autosomal recessive mutation leading to human ZAP-70-deficiency and a novel autosomal recessive mutation leading to human ITK-deficiency. I provide detailed clinical, immunological and biochemical analyses especially of TCR:CD3:ζ-signalling and compare my findings to the well-established Lck-/-, Zap-70-/- and Itk-/- murine models.
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Garshasbi, Masoud [Verfasser]. "Identification of 31 genomic loci for autosomal recessive mental retardation and molecular genetic characterization of novel causative mutations in four genes / Masoud Garshasbi." Berlin : Freie Universität Berlin, 2010. http://d-nb.info/1023623978/34.
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Barnhart, Kirstin Faye. "In vitro and in vivo analysis of differential gene expression between normal norfolk terrier dogs and those with an autosomal recessive mutation in KRT10." Texas A&M University, 2004. http://hdl.handle.net/1969.1/2671.
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Natural diseases caused by keratin mutations are rare and have only been reported in humans. We have recently identified a heritable skin disorder in Norfolk terriers caused by a mutation in KRT10. Affected dogs have a tendency to form shallow erosions or blisters following mild trauma, which is first noted after the birthing process. As the dogs age, they display generalized hyperpigmentation and scaling that is most severe in the axillary and inguinal regions. The main histologic and ultrastructural features include: marked hyperkeratosis, epidermal hyperplasia, prominent vacuolation of the upper suprabasal layers, eosinophilic intracytoplasmic aggregates (keratin bundles), numerous and frequently enlarged keratohyaline granules, and epidermal hyperplasia. Analysis of an extended pedigree through seven generations confirmed an autosomal recessive mode of inheritance. The keratin 10 mutation was defined as a G-T point mutation in intron 5 that affected splicing at the boundary of exon 4 and intron 5. The primary outcome of the mutation was a 35 bp deletion in exon 4 caused by use of a cryptic splice site. Real-time PCR quantitation of KRT10 confirmed that this mutation led to premature mRNA decay and an average 35-fold decrease in KRT10 message.
Organotypic cell culture techniques were used to establish in vitro models for normal and affected Norfolk terriers. After 21 days of culture, normal epidermis was cornified with a compact and multifocally parakeratotic stratum corneum. Affected epidermis largely reproduced the expected morphologic alterations. Immunoblotting and immunohistochemistry for keratin 10 protein and real-time PCR quantitation of KRT10 message showed significantly less keratin expression in vitro than in vivo suggesting that the differentiation program in vitro underwent significant alterations.
A diagnostic PCR assay was established for detection of the carrier state. Global analysis of gene expression between normal, carrier and affected dogs was performed with DermArray cDNA microarrays. Affected and carrier dogs showed differential regulation of 320 and 298 genes, respectively, between normal dogs. In affected dogs, 217 were upregulated and 103 were downregulated. In carrier dogs, 222 were upregulated and 76 were downregulated. 72 genes (65 upregulated, 7 downregulated) were altered in both affected and heterozygous dogs.
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Guillet, Stéphanie. "Monogenic predisposition to systemic lupus erythematosus and efferocytosis Impaired efferocytosis and Systemic Lupus Erythematosus in patients with autosomal recessive ACK1 and BRK Kinases deficiencies." Thesis, Sorbonne Paris Cité, 2019. http://www.theses.fr/2019USPCB003.
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Le Lupus Erythemateux disséminé (LED) est un ensemble de maladies auto-immunes caractérisées par la présence d'anticorps anti-nucléaires. La pathogenèse du lupus est inconnue à ce jour et les mécanismes de la maladie pourraient être multiples. Dans ce travail nous reportons l'identification de variants autosomaux récessifs, pertes de function, dans le domaine kinase de ACK1 et BRK respectivement, chez des patients atteints de LED de 2 familles non apparentées. Utilisant des macrophages dérivés d'iPSCs similaires aux macrophages résidents exprimant TIM4, nous montrons que la forme sauvage de ACK1 et BRK n'est pas requise pour la phagocytose de bactéries et de champignons, mais est nécessaire pour une efferocytose efficace, incluant la phagocytose mediée par l'actin de cellules apoptotiques par des macrophages humains et l'expression précoce de gène anti-inflammatoire induit par STAT3 et AKT et déclenché par l'exposition à des cellules apoptotiques. Ces résultats indiquent que l'activité kinase de ACK1 et BRK sont nécessaires pour la clearance immunologiquement silencieuse des cellules apoptotiques par les macrophages. Enfin ces données définissent un sous-groupe de patients atteints de LED avec un déficit génétique d'efferocytose qui pourrait bénéficier de thérapie ciblée dans le future<br>Systemic Lupus Erythematosus (SLE) is a collection of autoimmune diseases characterized by auto-antibodies against nuclear antigens. Pathogenesis of SLE remains unclear and disease mechanisms may be multiple. Here we report the identification of autosomal recessive loss-of-function variants in the kinase domain of ACK1 and BRK, in patients from two families with SLE. Using patients and controls iPSC-derived Tim4+ resident-like macrophages we find that wild-type ACK1 and BRK are dispensable for phagocytosis of bacteria and fungi, but are both required for efficient efferocytosis, including actin-mediated engulfment of apoptotic cells by human macrophages, and an early cell-autonomous anti-inflammatory gene expression program driven by AKT and STAT3 and triggered by apoptotic cells. These results indicate that ACK1 and BRK kinases activity are required for the immunologically silent clearance of apoptotic cells by macrophages and define genetic efferocytosis deficiency in a subset of SLE patients who may benefit from personalized therapy in the future
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Esmaeeli-Nieh, Sahar [Verfasser]. "Identification and functional characterization of a genetic defect in the kinetochore protein BOD1 associated with autosomal recessive mental retardation and oligomenorrhea / Sahar Esmaeeli-Nieh." Berlin : Freie Universität Berlin, 2011. http://d-nb.info/1026173965/34.
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Motazacker, Mohammad Mahdi [Verfasser]. "Identification of novel genetic loci for non-syndromic autosomal recessive mental retardation and molecular genetic characterization of a causative GRIK2 mutation / Mohammad Mahdi Motazacker." Berlin : Freie Universität Berlin, 2008. http://d-nb.info/102325929X/34.
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