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GAY, PHILIPPE. "Etude de l'erythropoietine au cours des thalassemies heterozygotes". Aix-Marseille 2, 1992. http://www.theses.fr/1992AIX20193.
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Rowe, Steven M., Cori Daines, Felix C. Ringshausen, Eitan Kerem, John Wilson, Elizabeth Tullis, Nitin Nair et al. "Tezacaftor–Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis". MASSACHUSETTS MEDICAL SOC, 2017. http://hdl.handle.net/10150/626280.
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BACKGROUND Cystic fibrosis is an autosomal recessive disease caused by mutations in the CFTR gene that lead to progressive respiratory decline. Some mutant CFTR proteins show residual function and respond to the CFTR potentiator ivacaftor in vitro, whereas ivacaftor alone does not restore activity to Phe508del mutant CFTR. METHODS We conducted a randomized, double-blind, placebo-controlled, phase 3, crossover trial to evaluate the efficacy and safety of ivacaftor alone or in combination with tezacaftor, a CFTR corrector, in 248 patients 12 years of age or older who had cystic fibrosis and were heterozygous for the Phe508del mutation and a CFTR mutation associated with residual CFTR function. Patients were randomly assigned to one of six sequences, each involving two 8-week intervention periods separated by an 8-week washout period. They received tezacaftor-ivacaftor, ivacaftor mono-therapy, or placebo. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from the baseline value to the average of the week 4 and week 8 measurements in each intervention period. RESULTS The number of analyzed intervention periods was 162 for tezacaftor-ivacaftor, 157 for ivacaftor alone, and 162 for placebo. The least-squares mean difference versus placebo with respect to the absolute change in the percentage of predicted FEV1 was 6.8 percentage points for tezacaftor-ivacaftor and 4.7 percentage points for ivacaftor alone (P<0.001 for both comparisons). Scores on the respiratory domain of the Cystic Fibrosis Questionnaire-Revised, a quality-of-life measure, also significantly favored the active-treatment groups. The incidence of adverse events was similar across intervention groups; most events were mild or moderate in severity, with no discontinuations of the trial regimen due to adverse events for tezacaftor-ivacaftor and few for ivacaftor alone (1% of patients) and placebo (<1%). CONCLUSIONS CFTR modulator therapy with tezacaftor-ivacaftor or ivacaftor alone was efficacious in patients with cystic fibrosis who were heterozygous for the Phe508del deletion and a CFTR residual-function mutation.
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Sousa, Ribeiro Maria Leticia de. "ß-Thalassemia and HB lepore heterozygotes: phenotype-genotype correlation". [Maastricht : Maastricht : Universiteit Maastricht] ; University Library, Maastricht University [Host], 1997. http://arno.unimaas.nl/show.cgi?fid=5822.
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Lebea, Phiyani Justice 1974. "Molecular characterisation of suspected heterozygotes of trimethylaminuria / Phiyani Justice Lebea". Thesis, Potchefstroom University for Christian Higher Education, 2002. http://hdl.handle.net/10394/13595.
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Trimethylaminuria (McKusick 602079) or Fish odour syndrome is inherited recessively
as a defect in hepatic nitrogen-oxidation of dietary derived trimethylamine (TMA), which
causes excess excretion of trimethylamine such that affected individuals have a body
odour reminiscent of rotten fish (Zhang et al., 1995). Trimethylaminuria is a result of
either partial or total incapacity to oxygenate trimethylarninuria to its oxide,
trimethylamine oxide (TMAO), by an enzyme known as the flavin-containing
monooxygenase 3 (FM03). Mutations in the gene of the major human liver enzyme
isoform, FM03, are responsible for causing trimethylaminuria (Akerman et al., 1999a
and Dolphin et al., 1997b ). Clinical symptoms of this disorder of metabolism include
fish-like to garbage-like odour of urine (trimethylaminuria), sweat (ishthyhidrosis) and
breath (halitosis) as well as psycho-clinical symptoms such as depression (Akerman et
al., l999a).
To establish the percentage of homo- and heterozygous trimethylaminuric individuals, a
screening programme was introduced for the Potchefstroom first year students.
Evaluation of the screening results through the liquid chromatograph-mass spectrometer,
which is based on the accurate determination of the TMA:TMAO ratio, showed a 1.46%
of mild trimethylaminuria individuals.
In this study, clinical symptoms induced by the loading test prior to urine evaluation of
the TMA:TMAO ratio is described. This was followed by isolation of the FM03 gene
from the blood of suspected individuals and subsequent amplification using the PCR.
Amplification was succeeded by restriction fragment length polymorphism analysis for
the determination of known common mutations throughout the different exons of the
FM03 gene. Single stranded conformation polymorphism and heteroduplex analysis
were performed to validate their applicability towards screening the FM03 gene.
Preliminary work was also done towards establishing the usage of the denaturing gel
gradient gel electrophoresis to screen the FM03 gene for aberrant sequences.
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Results obtained through restriction fragment length polymorphism indicated the possible
presence of the A52T mutation in ex on 3 of both patients that showed symptoms of mild
trimethylaminuria. The A52T mutation may be the most prevalent in the South African
population although more research still have to be done to investigate this possibility. The
main objective of this study was to establish the suitability of different methods towards
mutation screening of the FM03 gene. The methods attempted so far include polymerase
chain reaction, restriction fragment length polymorphism, single stranded conformation
polymorphism, heteroduplex analysis as well as denaturing gradient gel electrophoresis.
All methods were applicable, although to different extents and with different limitations
and resolutions. This study was a preliminary evaluation for a bigger study, which will
include family members of the suspected heterozygotes. In the subsequent study, all
nucleotide sequence fragments suspected of having mutations will be sequenced to
confirm the presence and the type of the mutation present.
xviiThesis, MSc, Potchefstroom University for Christian Higher Education 2002.
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Jansen, Natalie R. "Comparison of Health-Related Quality of Life Between Heterozygous Women with Fabry Disease, the General Population, and Patients with Chronic Disease". University of Cincinnati / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1109182046.
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Skjönsberg, Åsa. "Hereditary susceptibility to inner ear stress agents studied in heterozygotes of the German waltzing guinea pig /". Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-817-7/.
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MARISSAL, CARBONNIER CATHERINE. "Depistage des heterozygotes pour le bloc de la 21 hydroxylase dans une population de femmes adultes hirsutes". Lille 2, 1988. http://www.theses.fr/1988LIL2M001.
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Zhang, Mingcai. "The Role of New Mutations in Evolution: Identifying the Deleterious Effect of Heterozygotes and the Beneficial Effect on Adaptation to Salt-Stressed Environments in Drosophila Melanogaster". Bowling Green State University / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1276892040.
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Yardin, Marie Roseline, of Western Sydney Hawkesbury University, Faculty of Science and Technology e School of Science. "Genetic variation in Anadara trapezia (Sydney cockle) : implications for the recruitment of marine organisms". THESIS_FST_SS_Yardin_M.xml, 1997. http://handle.uws.edu.au:8081/1959.7/56.
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This project investigated the genetic composition of natural populations of Anadara trapezia in Australia at three spatial scales : i) microgeographic (within an estuary, 50 metres to ~ 6 kilometres); ii) microgeographic (within populations, less than 50 metres); and, iii) macrogeographic (hundreds of kilometres along the coast of Australia). Allozyme polymorphism surveys using cellulose acetate strips have revealed, from 43 enzymes screened, 18 putative polymorphic loci. Comparisons of levels of heterozygosity among enzyme structural groups showed no significant differences, however, monomers were significantly more variable as a group than multimers. Significant differences in the level and distribution of polymorphism among functional groups of enzymes were observed. It appears that selection may be acting at the molecular level, not only on a particular locus, but on a group of functionally similar loci. At the macrogeographic scale, significant departures from random mating were observed in most populations. Significant differences in allele distribution among populations of A. trapezia along the east coast of Australia were found. At the macrogeographic scale, heterogeneity of allele frequencies may depend upon the distance separating the populations and surface water currents. Differentiation among population groups in this study is attributed to changes in the direction of the East Australian Current combined with onshore countercurrents. The systematic status of the disjunct western Australian population of A. trapezia was also evaluated as compared with the east coast populations. No evidence of genetic, hence evolutionary divergence was found. The results have serious implications in the management of fisheries as erroneous assumptions in fisheries management models may lead to depletion and near extinction of marine species. The research stresses the necessity of sampling at multiple scales and replication strategies. It also highlighted the complexities researchers are faced with in studies of marine bivalves, such as the presence of null alleles, deficiencies of heterozygotes, apparent inbreeding and the small geographic scales governing population structure.Doctor of Philosophy (PhD)
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HADJ, SAHRAOUI NADIA. "Processus involutifs affectant les cellules de purkinje au cours du vieillissement chez deux mutants neurologiques : les souris heterozygotes staggerer (+/sg) et reeler (+/rl)". Paris 6, 1996. http://www.theses.fr/1996PA066779.
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La perte des neurones est consideree comme une des principales causes de la deterioration des fonctions du systeme nerveux central au cours du vieillissement. Cependant, les preuves experimentales d'une diminution du nombre des neurones au cours du vieillissement dit normal en particulier chez l'homme peuvent etre sujettes a caution tant a cause des methodes de comptage cellulaire utilisees qu'en raison de pathologies associees non evidentes. Un autre facteur pourrait jouer un role essentiel dans la variabilite des resultats de la litterature a savoir l'heterogeneite genetique des populations etudiees mais ce facteur est pour l'instant difficile a analyser chez l'homme. La souris, mammifere dont la genetique a ete particulierement bien etudiee est l'espece de choix pour mettre a l'epreuve cette hypothese ; nous avons donc quantifie une population de neurones facilement identifiables, les cellules de purkinje du cervelet, chez des mutants neurologiques de la souris pouvant offrir des modeles d'etude du vieillissement neurologique normal. En effet certains mutants neurologiques de la souris tels que staggerer, reeler, pcd (purkinje celle degeneration) presentent a l'etat homozygote des troubles locomoteurs visibles associes a des pertes neuronales massives dans la sphere olivo-cerebelleuse. Par exemple, chez le mutant homozygote staggerer (sg/sg), 60 a 90 % des cellules de purkinje (cp) sont absentes a un mois post-natal, cette perte s'associant a une atrophie macroscopiquement visible du cervelet et a la degenerescence des afferences de ces neurones. Il a ete montre recemment dans notre laboratoire, que l'heterozygote staggerer (+/sg), qui apparait cliniquement sain en apparence et dont le cervelet semble qualitativement normal, presentait cependant une perte de cp se developpant progressivement avec l'age pour atteindre 30 % chez l'animal de 12 mois. Ce resultat a suggere a ses auteurs que le gene staggerer pouvait constituer a l'etat heterozygote un gene de suscept ibilite au vieillissement neurologique normal du cervelet et cette hypothese a ete a l'origine du present travail. Dans un premier temps nous avons analyse l'evolution du nombre des cps chez le +/sg au dela de 12 mois, c'est a dire au cours du vieillissement proprement dit. Notre deuxieme objectif a ete de voir si l'hypothese emise pour le gene staggerer avait une valeur plus generale a savoir si d'autres genes pouvaient etre des genes de susceptibilite pour le vieillissement du cervelet. Nous avons donc etudie un autre exemple de mutant a l'etat heterozygote, le reeler, qui est lui aussi cliniquement sain en apparence. Le nombre des cps a ete estime che des +/sg femelles agees de 13, 18 et 24 mois et des heterozygotes reeler (+/rl) males et femelles de 3, 16 et 26 mois. Dans les deux groupes, les cervelets inclus dans la paraffine ont ete decoupes dans le plan sagittal en coupes seriees. Les cps ont ete comptes toutes les 40 coupes sous un microscope photonique a un grossissment de x1250. Les resultats bruts des comptages cellulaires ont ete corriges selon la methode de hendry. Chez le +/sg de 13 et 18 mois, il y a une diminution significative du nombre de cp (22 a 26 %) par rapport aux temoins (+/+) du meme age. Ce nombre ne change plus chez les +/sg de 13 et 18 mois alors qu'il diminue chez les temoins de 24 mois de maniere identique a celle des +/sg de 13 et 18 mois. Comme les animaux +/+ de la lignee c57bl/6j, les +/+ de la lignee balb/c (temoins des reelers) presentent une perte de cp qui apparait entre 16 et 26 mois et touche environ un quart de la population des cps chez les males. Toujours chez les males, les +/rl presentent un deficit de 16 % du nombre de cp des 3 mois qui atteint 24 % a 16 mois. Chez les femelles en revanche, il n'y a aucune perte de cp significative avec l'age aussi bien chez les sauvages que chez les heterozygotes. Ces resultats confirment donc l'hypothese que le gene staggerer provoque a l'etat heterozygote un vieillissement precoce du cervelet et que cette vulnerabilite des cps se retrouve aussi dans un autre exemple, l'heterozygote reeler. Dans la troisieme partie de notre travail, nous nous sommes demande si les effets de telles mutations se limitaient a la disparition d'un certain pourcentage de cp ou si elles entrainaient egalement des phenomenes involutifs au niveau des cps qui n'etaient pas affectees par le processus de mort neuronale. Nous avons donc recherche des anomalies de la morphologie des cellules de purkinje survivantes chez des heterozygotes staggerer et leur evolution en fonction de l'age. Pour cela nous avons compare la morphologie des arbres dendritiques des cps d'animaux de 4, 12 et 22 mois de +/sg et de +/+ grace a une methode semi-quantitative qui permet d'examiner un grand nombre de cellules en tenant compte de 9 parametres morphologiques decrivant l'arbre dendritique. Il apparait que la mutation staggerer entraine des 4 mois, une involution dendritique tant en largeur qu'en hauteur qui s'ag
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Gonçalves, Rafaelle Ribeiro. "ESTRUTURA GENÉTICA DE POPULAÇÕES NATURAIS DE Parides agavus (LEPIDOPTERA; PAPILIONIDAE) DA REGIÃO CENTRAL DO RIO GRANDE DO SUL, BRASIL". Universidade Federal de Santa Maria, 2007. http://repositorio.ufsm.br/handle/1/11175.
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The population structure from the genetic and evolutive view-point tries to quantify the morphologic and quantitative variability existing among the individuals, their reproductive behavior, and gene flow patterns, and the adaptative strategies to the local environment. The present study had as objective to describe the genetic population structure and the genetic variability found in natural populations of Parides agavus Santa Maria region.
For the study it was utilized polyacrylamide gel electrophoresis, for isozymes. Eighty-eight P.
agavus adult individuals were collected in three localities in Santa Maria. Eleven genic loci were obtained totalizing 26 alleles. The genetic diversity levels presented by the populations of P. agavus, can be considered high if they are compared with other lepidoptera species. The index of fixation for the population set presented positive value suggesting the bias panmixia in the population set. The mean FST was low, indicating little genetic differentiation among
the sampling populations suggesting high gene flow or that these ones originated themselves for irradiation of same population in the past. The genetic divergence between the pairs of populations agree with the values found to the genetic distance, these data can be effect of high dispersal specie or from a connexity of the studied areas, in the past. The gene flow estimated is sufficient to maintain the low genetic differentiation among the populations of this species.A estrutura populacional do ponto de vista genético e evolutivo procura quantificar a variabilidade morfológica e quantitativa existente entre os indivíduos, seu comportamento reprodutivo, os padrões de fluxo gênico, e as estratégias adaptativas aos ambientes locais. O presente estudo teve como objetivo descrever a estrutura genética populacional e a variabilidade genética encontrada em populações naturais de Parides agavus da região de Santa Maria. Para o estudo utilizou-se eletroforese em gel de poliacrilamida para alozimas. Foram coletados 88 indivíduos adultos de P. agavus em três localidades de Santa Maria. Foram obtidos 11 locos gênicos totalizando 26 alelos. Os níveis de diversidade genética apresentados pelas populações de P. agavus, podem ser considerados altos se comparados com outras espécies de lepidópteros. O índice de fixação para o conjunto das populações apresentou valor positivo sugerindo desvio da panmixia no conjunto das populações. O FST médio foi baixo indicando pouca diferenciação genética entre as populações amostradas sugerindo um alto fluxo gênico entre as populações, outra suposição sugere que estas se originaram por radiação de uma mesma população no passado. A divergência genética entre os pares de populações concorda com os valores encontrados para a distância genética, estes dados podem ser efeitos da alta dispersão da espécie, ou de uma conectividade das áreas estudadas, no passado. O fluxo gênico aparente médio estimado é suficiente para manter a baixa diferenciação genética entre as populações desta espécie.
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Pinto, Louise Lapagesse de Camargo. "Avaliação de manifestações clínicas e laboratoriais em heterozigotas para mucopolissacridose tipo II". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2009. http://hdl.handle.net/10183/19093.
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Introdução: A maioria das doenças lisossômicas são herdadas como traços recessivos, mas a mucopolissacaridose tipo II (MPS II) é de herança ligada ao cromossomo X. As doenças ligadas ao cromossomo X possuem um importante impacto para as famílias devido ao risco que as heterozigotas apresentam em ter um filho afetado. A maioria das heterozigotas para as doenças ligadas ao cromossomo X são clinicamente assintomáticas. Em relação à MPS II somente dez mulheres afetadas foram relatadas na literatura. Entretanto, nenhum estudo foi realizado para a avaliação da presença de sinais sutis da doença nessas heterozigotas. Objetivo: o objetivo principal desse estudo foi a identificação de sinais clínicos sutis e bioquímicos relacionados à MPS II nas heterozigotas para essa doença e adicionalmente estabelecer a associação desses achados com o padrão de inativação do cromossomo X. Métodos: esse foi um estudo observacional e transversal. Essas mulheres foram classificadas como heterozigotas e não heterozigotas baseadas na análise molecular do gene da iduronato sulfatase (IDS). Ambos grupos foram comparados com relação às seguintes variáveis: dados clínicos, achados do exame físico, cariótipo, padrão de inativação do cromossomo X (ensaio HUMARA), atividades da IDS em leucócitos e plasma, níveis de glicosaminoglicanos na urina, tomografia computadorizada de abdomen e coluna e ressonância magnetica de crânio. Resultados: Quarenta mulheres pertencentes a 24 famílias foram avaliadas. De acordo com a análise do DNA 22 foram classificadas em heterozigotas e 18 em não heterozigotas. Não foi encontrada nenhuma anormalidade no exame físico (n=40), cariótipo (n=31/40) ou na TC de coluna (n=31/40). A incidência de abortamento também não apresentou diferenças entre essas mulheres. Entretanto, a atividade da IDS em plasma (p<0,001) e em leucócitos (p<0,001) apresentaram níveis inferiores nas heterozigotas. A correção de Bonferroni foi aplicada e não foi encontrada nenhuma diferença entre os grupos dentre as variáveis analisadas. Também em relação ao padrão de inativação do cromossomo X não foi observada diferença esntre as heterozigotas e não heterozigotas. Conclusões: Esse é o primeiro estudo sistemático realizado em heterozigotas para MPS II. Não foi encontrada nenhuma evidência de manifestações clínicas sutis ou sinais radiológicos da doença MPS II nessas mulheres. Nossos achados sugerem que não existe relação entre a ausência dos sinais clínicos nessas mulheres e a ocorrência de um padrão favorável de desvio da inativação do cromossomo X. Esses dados sugerem que a MPS II apresenta uma baixa penetrância nas heterozigotas.Introduction: Most lysosomal diseases are inherited as recessive traits, but muchopolysaccharidosis type II (MPS II) presents X-linked inheritance. The X-linked disorders have an important impact for families because the risk heterozygous present of having an affected child. Most heterozygotes for X-linked disorders are clinically asymptomatic. Regarding MPS II only ten affected females have been reported in the literature. However, none study has been taken in order to evaluate subtle signs of the disease in heterozygotes. Objective: The main objective of this study was to identify subtle clinical and biochemical signs of MPS II in heterozygotes for this disease, and to correlate the findings with the pattern of X chromosome inactivation presented by these women. Methods: This was an observational, transversal and controlled study. The women were classified as heterozygote or non-heterozygote based on molecular analysis of the iduronate sulfatase (IDS) gene. Both groups were compared between regarding clinical data, physical exam findings, karyotype, pattern of X inactivation (HUMARA assay), IDS activity in leukocytes and plasma, glycosaminoglicans levels in urine, computadorized tomography scans of abdomen and spine, and brain magnetic resonance imaging. Results: Forty women from 24 families were evaluated. According to DNA analysis, 22 women were classified as heterozygote and 18 as non-heterozygotes. We did not found any abnormality in physical examination (n=40), karyotype (n=31/40) or spine CT scans (n=31/40). The incidence of miscarriage also did not differ between these females. However, IDS activities in plasma (p<0.001) and in leukocyte (p<0.001) were lower in heterozygotes. Applying the Bonferroni’s correction, we did not find any difference between the groups regarding the variables analyzed. Also the pattern of X chromosome inactivation was not different between heterozygotes and non-heterozygotes. Conclusion: This is the first systematic study performed in heterozygotes for MPS II. We did not find any evidence of subtle clinical manifestations or radiological signs of MPS II disease in these females. Our findings suggest that there is no relation between the absence of clinical signs in these women and the occurrence of a favorable skewing pattern of X chromosome inactivation. This data suggests that MPS II is a disease which shows low penetrance in heterozygotes.
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Huppmann, Marceline. "Lungenmechanische Charakterisierung von heterozygoten ABCA3-Knockout-Mäusen". Diss., lmu, 2011. http://nbn-resolving.de/urn:nbn:de:bvb:19-133099.
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Müller, Eva. "Klinische und funktionelle Charakterisierung einer stark wachstumsretardierten Patientin mit einer zusammengesetzten heterozygoten Pericentrinmutation und einer heterozygoten IGF1-Rezeptor Mutation". Doctoral thesis, Universitätsbibliothek Leipzig, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-131321.
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Die menschliche Entwicklung ist charakterisiert durch ein rasches fetales Wachstum, ein langsames postnatales Wachstum, ein kontinuierliches Wachstum im Laufe der Kindheit sowie einen Wachstumsschub während der Pubertät.
In den letzten Jahren wurde gezeigt, dass Mutationen in den Genen des Pericentrins (PCNT) und des Insulin-like growth factor-1 Rezeptors (Insulin ähnlicher Wachstumsfaktor Typ 1 Rezeptor, IGF1R) seltene Auslöser von prä- und postnataler Wachstumsrestriktion darstellen können. In dieser Arbeit wird eine stark wachstumsretardierte Patientin mit zusammengesetzter heterozygoter PCNT-Mutation und heterozygoter IGF1R-Mutation beschrieben. Ziel dieser Arbeit war zum einen die ausführliche klinische Charakterisierung der Patientin. Zum anderen sollte auf zellulärer Ebene überprüft werden, inwieweit die genannten Mutationen den Phänotyp der Patientin erklären. Um die funktionellen Zusammenhänge zu untersuchen, wurden in vitro Assays durchgeführt. Hierfür standen neben mit dem mutierten Rezeptor transfizierte IGF1R-defiziente Mausfibroblasten (R--Zellen) auch humane Fibroblasten zur Verfügung. Es wurden die totale und die extrazelluläre Rezeptorexpression, die IGF1 induzierte Stimulierung und die Signaltransduktion des mutierten IGF1R untersucht. Weiterhin wurde die proliferative Kapazität der Patientenfibroblasten analysiert. Die Ergebnisse dieser Analysen ergaben keine relevanten Funktionseinschränkungen des mutierten IGF1R. Demgegenüber steht eine reduzierte Zellproliferation der Patientenfibroblasten. Die zugrunde liegenden Mechanismen der verminderten Proliferationskapazität sind womöglich den PCNT-Mutationen zuzurechnen. In Versuchen zur IGF1 induzierten Proliferationssteigerung konnte die Proliferation der Patientenfibroblasten zwar kurzfristig stimuliert werden, bei längerer IGF1-Stimulation konnte jedoch das bestehende Proliferationsdefizit nicht ausgeglichen werden. Die genauen molekularbiologischen Auswirkungen der PCNT-Mutation in Bezug auf den ausgeprägten Phänotyp der Patientin müssen in zukünftigen Arbeiten noch weiter aufgeklärt werden.
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Price, Jared Calvin. "The Bioluminescence Heterozygous Genome Assembler". BYU ScholarsArchive, 2014. https://scholarsarchive.byu.edu/etd/4346.
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High-throughput DNA sequencing technologies are currently revolutionizing the fields of biology and medicine by elucidating the structure and function of the components of life. Modern DNA sequencing machines typically produce relatively short reads of DNA which are then assembled by software in an attempt to produce a representation of the entire genome. Due to the complex structure of all but the smallest genomes, especially the abundant presence of exact or almost exact repeats, all genome assemblers introduce errors into the final sequence and output a relatively large set of contigs instead of full-length chromosomes (a contig is a DNA sequence built from the overlaps between many reads). These problems are dramatically worse when homologous copies of the same chromosome differ substantially. Currently such genomes are usually avoided as assembly targets and, when they are not avoided, they generally produce assemblies of relatively low quality. An improved algorithm for the assembly of such data would dramatically improve our understanding of the genetics of a large class of organisms. We present a unique algorithm for the assembly of diploid genomes which have a high degree of variation between homologous chromosomes. The approach uses coverage, graph patterns and machine-learning classification to identify haplotype-specific sequences in the input reads. It then uses these haplotype-specific markers to guide an improved assembly. We validate the approach with a large experiment that isolates and elucidates the effect of single nucleotide polymorphisms (SNPs) on genome assembly more clearly than any previous study. The experiment conclusively demonstrates that the Bioluminescence heterozygous genome assembler produces dramatically longer contigs with fewer haplotype-switch errors than competing algorithms under conditions of high heterozygosity.
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Willer, Mario. "Molekulargenetische Untersuchungen zur Expression von Sequenzveränderungen im REP-1-Gen bei heterozygoten Trägerinnen". kostenfrei, 2008. http://www.opus-bayern.de/uni-regensburg/volltexte/2009/1179/.
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Foucher, Karine. "Rôle de la mutation H63D du gène HFE : étude comparative de 83 sujets hétérozygotes composites C282Y/H63D et de 52 hétérozygotes simples C282Y". Montpellier 1, 1999. http://www.theses.fr/1999MON11132.
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Maier, Esther Maria. "X-Inaktivierung bei heterozygoten Überträgerinnen X-chromosomal gebundener Adrenoleukodystrophie". Diss., lmu, 2002. http://nbn-resolving.de/urn:nbn:de:bvb:19-1606.
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Bailey, K. J. "Control of photosynthesis by PEP carboxylase in leaves of Amaranthus edulis". Thesis, University of Sheffield, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.284761.
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Miyoshi, Hiroyuki. "Gastrointestinal hamartomatous polyposis in Lkb1 heterozygous knockout mice". Kyoto University, 2003. http://hdl.handle.net/2433/148260.
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Schatz, Stephanie. "X-Inaktivierung bei heterozygoten Patientinnen bezüglich X-chromosomal vererbtem Morbus Fabry". Diss., lmu, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-149332.
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Craigie, Eilidh. "Investigating mechanisms of salt-sensitive hypertension in 11β-HSD2 heterozygote mice". Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5565.
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The mineralocorticoid hormone, aldosterone, classically acts via the Mineralocorticoid Receptor (MR) to promote sodium transport in aldosterone target tissues, such as the kidney, thereby controlling long-term electrolyte homeostasis and blood pressure (BP). Aldosterone biosynthesis by the adrenal gland is regulated by a negative feedback loop called the Renin Angiotensin Aldosterone System (RAAS). The glucocorticoid cortisol (corticosterone in rodents), which has a very similar structure to aldosterone, shares with aldosterone an equal affinity for the MR. Typically, plasma cortisol levels are approximately 1000-fold higher than plasma aldosterone, and so the ligand specificity for aldosterone must be imposed on MR by other, non-structural, means. This specificity is important in order to retain electrolyte and BP balance within the control of the RAAS. The co-localisation of the enzyme 11β-Hydroxysteroid Dehydrogenase Type 2 (11β-HSD2) with the MR in aldosterone target tissues provides the MR with the aldosterone specificity it inherently lacks. 11β-HSD2 achieves this by converting active cortisol to its inactive 11-keto metabolite, cortisone (dehydrocorticosterone in rodents). In humans with the monogenetic Syndrome of Apparent Mineralocorticoid Excess (SAME), inactivating mutations in the HSD11B2 gene allows cortisol unregulated access to the MR. Resultant symptoms include severe hypertension and life-threatening hypokalemia. Individuals heterozygous for SAME display no overt phenotypes. However, some studies have associated SAME heterozygosity and loss-of-function polymorphisms within the HSD11B2 gene with essential and/or salt-sensitive hypertension in the general population. Targeted disruption of the Hsd11b2 gene in mice (Hsd11b2-/-) faithfully reproduces with all the major phenotypes of SAME patients. Mice heterozygote for the targeted gene (Hsd11b2+/-) have no phenotype and display a normal BP. In the present study, Hsd11b2+/- mice were used to explore the relationship between reduced 11β-HSD2 enzyme activity and salt-sensitive hypertension. On a high salt diet, Hsd11b2+/- mice were found to have increased BP and impaired natriuresis, compared to wild-type controls (Hsd11b2+/+). Further studies used pharmacological blockade of the Epithelial Sodium Channel (ENaC) and MR to ascertain the contributions of these pathways towards the observed phenotypes. These identified a deregulation of ENaC activity pertaining to an inability to regulate sodium appropriately. Investigations into the contributions of the RAAS and the Hypothalamus Pituitary Adrenal (HPA) axis have revealed valuable insights into their roles in this model. There is an implication that the RAAS has increased sensitivity in Hsd11b2+/-, further exacerbated by increased dietary sodium, and that the regulation of corticosteroids may also be altered. Novel observations have suggested that oxidative stress in response to a high salt diet could also be involved, as a study administering an antioxidant drug in conjunction with a high salt diet prevented the manifestation of a phenotype in Hsd11b2+/-. Finally, the generation of a floxed Hsd11b2 targeting construct for tissue-specific deletion of 11β-HSD2 will allow future studies into the contributions of specific 11β-HSD2 expression sites (such as the kidney) towards the phenotypes of both homozygous and heterozygous mice.
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GIRARD, VALERIE. "Expression du genotype 10 kb dans l'hypercholesterolemie familiale heterozygote au quebec". Besançon, 1992. http://www.theses.fr/1992BESA3054.
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Dupin, André. "Zur Transglutaminase-Aktivität der Untereinheit A des Faktor XIII in plättchenarmem und plättchenreichem Plasma sowie in Thrombozytenkonzentraten bei Patienten mit heterozygotem, doppelt heterozygotem und homozygotem Faktor-XIII-Mangel". [S.l.] : [s.n.], 2004. http://archiv.ub.uni-marburg.de/diss/z2004/0395/.
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Wallborn, Tillmann. "Klinisches Erscheinungsbild und zugrundeliegende molekularbiologische Mechanismen der heterozygoten V599E-IGF-I Rezeptormutation". Doctoral thesis, Universitätsbibliothek Leipzig, 2012. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-90100.
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Untersuchungen haben gezeigt, dass unterdurchschnittlich leichte Neugeborene für zahlreiche Erkrankungen ein erhöhtes Risiko tragen. Beschrieben ist unter anderem das vermehrte Auftreten psychosozialer Probleme sowie metabolischer und kardiovaskulärer Spätfolgen. Inzwischen sind zahlreiche mögliche Ursachen einer intrauterinen und postnatalen Wachstumsretardierung beschrieben worden. Unter diesen Ursachen finden sich auch genetische Veränderungen von Proteinen der endokrinologischen Wachstumsregulierung. So wurden Mutationen im GH1 Gen, in Entwicklungsgenen von GH produzierenden Zellen, im IGF-I Gen und schließlich auch im IGF-I Rezeptor Gen identifiziert. Mutationen im letztgenannten Gen stellen den neuesten Forschungszweig dar und wurden bisher weltweit bei lediglich 19 Patienten festgestellt.
Mit dieser Arbeit wird ein weiterer Patient mit einer heterozygoten IGF-I Rezeptormutation beschrieben. Neben einer ausführlichen klinischen Beschreibung war die Analyse der Kausalzusammenhänge von Mutation und klinischem Bild Hauptziel dieser Studie. Über eine ausgeprägte intrauterine und postnatale Wachstumsretardierung hinaus präsentierte die betroffene Patientin eine mentale Entwicklungsverzögerung. Durch verschiedene molekularbiologische Methoden konnte eine gestörte intrazelluläre Prozessierung des veränderten Rezeptorproteins nachgewiesen werden. Beobachtet wurde eine fehlende Zelloberflächenexpression aufgrund einer Retention von Rezeptorvorstufen im Endoplasmatischen Retikulum. Damit wurde ein neuer Mechanismus der IGF-I Resistenz beschrieben.
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Flemming, Gunter. "Funktionelle Charakterisierung heterozygoter GLI2 missense Mutationen bei Patienten mit multiplem hypophysären Hormonmangel". Doctoral thesis, Universitätsbibliothek Leipzig, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-130953.
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Der GLI2-Transkriptionsfaktor ist eines der Haupt Effektor-Proteine des Sonic Hedgehog (SHH)-Signalweges und hat vermutlich eine Schlüsselfunktion in der Entwicklung der Hypophyse. Genomische GLI2-Veränderungen welche zu abgeschnittenen Proteinen führten, wurden beschrieben als Ursache für Holoprosenzephalie (HPE) oder HPE-ähnliche Veränderungen, teilweise in Verbindung mit einer Hypophysenunterfunktion.
Ziel dieser Arbeit war die Ermittlung der Frequenz von GLI2-Mutationen in Patienten mit multiplem hypophysärem Hormonausfall (multiple pituitary hormone deficiency, MPHD) und eine funktionelle Untersuchung der gefunden Mutationen mittels Transkriptionsaktivitäts-Untersuchungen durch funktionelle Luciferase assays.
Hierfür wählten wir Teilnehmer der GeNeSIS (Genetics and Neuroendocrinology of Short Stature International Study)-Studie. Patienten bei denen bereits Mutationen eines der
etablierten Gene für MPHD nachgewiesen wurde, wurden ausgeschlossen. Insgesamt haben wir 168 Patienten mit MPHD untersucht. Bei allen Patienten waren mindestens ein GH- und ein TSH-Mangel dokumentiert, Auffälligkeiten in der zentralen Bildgebung mittels cMRT wurden bei 96 Patienten angegeben.
In fünf Studienteilnehmern wurden vier verschiedene heterozygote missense Varianten nachgewiesen, hiervon wurden zwei bislang noch nicht in der Literatur beschrieben. Eine Variante, pR516P, führte in den in-vitro Experimenten zu einem kompletten Verlust der Proteinaktivität. Zusätzlich zu einem Wachstumshormonmangel hatte der Träger dieser Mutation einen Mangel an TSH und der Gonadotropine, sowie einen nichtdeszendierten Hypophysenhinterlappen und eine Polydaktylie, aber keine ersichtlichen Mittelliniendefekte.
Anhand der funktionellen Untersuchung konnten wir erstmalig nachweisen, dass ein heterozygoter Aminosäuren-Austausch im GLI2-Protein zu einer möglichen Funktionseinschränkung der Transkriptionsaktivität führen kann und somit die Ursache für MPHD mit milden extrahypophysären Auffälligkeiten sein könnte. Der Phänotyp von GLI2-Mutationen ist variabel und die Penetranz ist unvollständig. GLI2-Mutationen sind assoziiert mit einer Hypoplasie des Hypophysenvorderlappens und treten gehäuft mit einem ektopen Hypophysenhinterlappen auf.
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Schäfer, Sabine [Verfasser]. "Testikuläre Teratome in AP-2γ heterozygoten Mäusen / Sabine Schäfer. Mathematisch-Naturwissenschaftliche Fakultät". Bonn : Universitäts- und Landesbibliothek Bonn, 2011. http://d-nb.info/1018373462/34.
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Hood, S. M. "Colour perception in females heterozygous for a colour deficiency". Thesis, University of Cambridge, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604207.
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Initial experiments examine the performance of heterozygous females on standard tests of colour vision. The results of these tests do not provide convincing evidence to support the hypothesis that carriers share in the colour deficiencies of their fathers and sons. Colour vision is thought to depend upon two subsystems that remain parallel and independent in the early stages of visual processing. I examine the relative organizing power of these two subsystems and find that carriers of a colour deficiency cannot be considered as one population. For small element separations, the relative organizing power of the L-M subsystem is reduced for deutan carries in comparison to both colour normals and protan carriers. In contrast, for large element separations, there is no difference between colour normals and carriers of any colour deficiency. Individuals with more symmetrical L: M cone ratios are often supposed to exhibit better red-green chromatic discrimination. As heterozygosity will not lead to symmetrically extreme L: M cone ratios in protan and deutan carriers, I propose that the L-M subsystem of deutan carries is less sensitive owing to the more extreme skewing of the L: M cone ratio in such carriers; the reduction in sensitivity will be most evident at high spatial frequencies. Red-green chromatic spatial Contrast Sensitivity Functions (CSF) are measured to test this hypothesis. At spatial frequencies comparable to those of the smallest element separation used in examining the relative saliency of the two subsystems of colour vision, deutan carriers have lower red-green contrast sensitivity than both protan carriers and colour normals. Further experiments were conducted on a new subject population to verify these findings. The results confirm that deutan carriers exhibit poorer red-green contrast sensitivity than colour normals and suggest that individuals with more symmetrical L: M cone ratios do exhibit better red-green contrast sensitivity.
29
GIORDANO, FRANCOISE. "Maladie de fabry : forme heterozygote d'expression differente chez deux soeurs jumelles monozygotes". Toulouse 3, 1989. http://www.theses.fr/1989TOU31535.
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Lasica, Rick, e Ashley Loy. "Cost-Effectiveness Analysis of PCSK9 Inhibitors for the Treatment of Heterozygous Familial Hypercholesterolemia". The University of Arizona, 2017. http://hdl.handle.net/10150/624203.
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Class of 2017 AbstractObjectives: To determine the cost-effectiveness of proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors with high-intensity statins compared to high-intensity statins alone for the treatment of heterozygous familial hypercholesterolemia (HeFH). Methods: A Markov model was built through TreeAge Pro to model two groups: patients taking PCSK9 inhibitors with high-intensity statins or high-intensity statins alone. For each group, there were five health states that patients could be in: well, unstable angina, myocardial infarction, ischemic stroke, or death. The data used in the model were extracted from published clinical trials evaluating PCSK9 inhibitors and statins. Results: For the primary analysis, the overall cost and effectiveness was $31,390.93 and 23.01 for the statin alone group and $362,798.50 and 24.32 for the PCSK9 with statin group, respectively. The incremental cost, incremental QALY, and incremental cost-effectiveness ratio (ICER) was $331,407.60, 1.31 QALYs, and $252,833.60/QALY, respectively. Conclusions: Since the calculated ICER was higher than the pre-established threshold of $150,000, the results from our primary analysis suggest that treatment of patients with HeFH with a PCSK9 inhibitor and a high-intensity statin is not cost effective, compared to treatment with a high-intensity statin alone. However, when certain parameters (cost of PSCK9 and mortality rate) were adjusted in the secondary analyses, these agents appear to be cost-effective.
31
Müller, Eva [Verfasser], Wieland [Akademischer Betreuer] Kiess, Jürgen [Akademischer Betreuer] Klammt, Roland [Gutachter] Pfäffle e Jürgen [Gutachter] Kratzsch. "Klinische und funktionelle Charakterisierung einer stark wachstumsretardierten Patientin mit einer zusammengesetzten heterozygoten Pericentrinmutation und einer heterozygoten IGF1-Rezeptor Mutation. / Eva Müller ; Gutachter: Roland Pfäffle, Jürgen Kratzsch ; Wieland Kiess, Jürgen Klammt". Leipzig : Universitätsbibliothek Leipzig, 2014. http://d-nb.info/1238599869/34.
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Huppmann, Marceline [Verfasser], e Andreas W. [Akademischer Betreuer] Flemmer. "Lungenmechanische Charakterisierung von heterozygoten ABCA3-Knockout-Mäusen / Marceline Huppmann. Betreuer: Andreas W. Flemmer". München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2011. http://d-nb.info/1015169775/34.
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Le, Gallais Daniel. "L'aptitude physique des porteurs du trait drépanocytaire". Montpellier 1, 1990. http://www.theses.fr/1990MON14002.
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34
Souweine, Bertrand. "Beta thalassemie heterozygote et grossesse : a propos d'une enquete effectuee en haute-corse". Aix-Marseille 2, 1988. http://www.theses.fr/1988AIX20529.
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Fritz, Andrea Maria. "Langzeiteinfluss der früh-postnatalen Ernährung auf den Körperfettgehalt von adulten Wildtyp- und heterozygoten Zuckerratten". Wettenberg : VVB Laufersweiler, 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=974923052.
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Hitzegrad, Anna [Verfasser]. "Familiäres-Mittelmeerfieber-Patienten mit heterozygotem Genotyp: eine Patientengruppe mit einem milderen Verlaufsprofil / Anna Hitzegrad". Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2018. http://d-nb.info/1170877044/34.
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Ribeiro, Leslie. "Characterization of the respiratory phenotype of the Late Gestation Lung 1 («Lgl1») heterozygote mouse". Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=32607.
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Bronchopulmonary dysplasia (BPD), a disease characterized by an arrest in alveolar development, remains one of the leading causes of morbidity in very low birth weight newborns [1, 2]. Insight into the mechanisms and genes involved in alveolarization could be used to better understand the lung pathophysiology of this disease and help with the development of new treatment interventions. Lgl1, is a developmentally regulated, glucocorticoid induced, secreted glycoprotein in the lung [3]. In O2 toxicity animal models of BPD, Lgl1 levels are reduced and return to normal during recovery in air [4]. To determine if a deficiency of Lgl1 is associated with arrested alveolarization and contributes to the pathophysiology of BPD, an Lgl1 knockout mouse model was created. Lgl1 deficiency revealed a complex phenotype including: goblet cell hyperplasia, mucus production, increase expression of interleukins 4 and 13, disruption of lung development, elastin fragmentation and disruption of lung function suggesting that Lgl1 deficiency may contribute to BPD in the neonatal period.La dysplasie bronchopulmonaire (DBP), une maladie caractérisée par l'arrêt du développement alvéolaire, demeure une des causes principales de morbidité chez les nouveau-nés de faible poids [1, 2]. Plus d'informations sur les mécanismes et les gènes impliqués dans l'alvéolarisation sont nécessaires afin de mieux comprendre la physiopathologie de cette maladie et aider au développement de nouvelles interventions thérapeutiques. Lgl1 est une glycoprotéine sécrétée dans le poumon qui est induite par les glucocorticoïdes et finement régulée lors du développement [3]. Dans les modèles animaux de toxicité d'O2 qui mimique la DBP, les niveaux de Lgl1 sont réduits puis redeviennent normaux lors de la récupération dans l'air [4]. Afin de déterminer si une déficience de Lgl1 est associée à une arrestation de l'alvéolarisation et contribue à la physiopathologie de la DBP, une souris mutante pour le gène Lgl1 a été générée. Un déficit de Lgl1 a révélé un phénotype complexe, incluant notamment : l'hyperplasie des cellules caliciformes, la production de mucus, l'augmentation de l'expression des interleukines 4 et 13, la perturbation du développement pulmonaire, la fragmentation de l'élastine et la perturbation de la fonction mécanique du poumon suggérant que la carence de Lgl1 pourrait contribuer à la DBP dans la période néonatale.
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Kongmanas, Kessiri. "Significance of sulfogalactosylglycerolipid in male fertility: Studies using Cgt heterozygous mice". Thesis, University of Ottawa (Canada), 2008. http://hdl.handle.net/10393/27996.
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Sulfogalactosylglycerolipid (SGG) is a sulfoglycolipid present specifically at a substantial level in mammalian male germ cells. It has been shown to function as an adhesion molecule important for sperm-egg interaction and a structural lipid involved in formation of sperm lipid rafts during capacitation in vitro. Due to the unique characteristics and functions, SGG can potentially serve as a biomarker for sperm fertility as well as a target for development of a non-hormonal contraceptive. To confirm the in vivo roles of SGG, we sought for transgenic mice with reduced amounts of sperm SGG. Cgt knockout male mice, transgenetically deficient in UDP-galactose:ceramide galactosyltransferase (CGT), an enzyme involved in SGG synthesis, are infertile due to spermatogenesis disruption. However, the Cgt+/- males can still produce sperm and sire offspring. We hypothesized that Cgt+/- males, expected to have reduced SGG amounts, would have compromised fertilizing ability and could serve as in vivo models for studying roles of SGG in fertilization and spermatogenesis. Unexpectedly, our results revealed that Cgt+/- males exhibited unimpaired spermatogenesis and fecundity. Moreover, the levels of SGG as well as lipid profiles of sperm and testes of Cgt+/- mice were similar to those of the wild type, suggesting that compensatory mechanisms must have occurred to maintain SGG levels in the Cgt+/- mice. Although these results revealed that Cgt+/- mice could not be used as the animal models, they implicated significance of normal testis and sperm SGG levels in maintaining normal spermatogenesis and fertility. The possible compensatory mechanisms regulating SGG levels were further investigated in Cgt+/- mice. As expected, only half of Cgt mRNA expression level of the wild type was transcribed in the Cgt+/- testes; however, testicular CGT polypeptides as well as their enzymatic activities in the Cgt+/- mice were found at a comparable level to those of the wild type. On the other hand, no change was found in terms of mRNA levels, polypeptide levels or enzymatic activities of arylsulfatase A (ASA), the enzyme responsible for SGG degradation in the testis. In conclusion, the compensatory mechanisms for SGG level adjustment in Cgt +/- mice occurred through the biosynthetic pathway, rather than the degradation pathway, by increasing the CGT polypeptide expression level. Therefore, identification of specific spermatogenic cell stages, contributing to normal expression levels of CGT and SGG in the Cgt+/- testes warrants further studies, as these studies should provide useful information regarding CGT and SGG importance during male germ cell development. In addition, a new approach to produce the animal models that can produce sperm with reduced SGG levels should be attempted. The RNA interference (RNAi) techniques may be tried to achieve this goal.
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Bankar, Girish. "Heterozygous rho kinase2 deficinecy increases whole body insulin sensitivity in mice". Thesis, University of British Columbia, 2013. http://hdl.handle.net/2429/44092.
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The incidence of obesity and type 2 diabetes is increasing worldwide. Impaired insulin sensitivity in peripheral tissues has been considered one of the major causes of whole body insulin resistance. Previous in vitro and in vivo studies have shown that the RhoA/ROCK pathway regulates the insulin signaling pathway. Two isoforms of Rho kinase (ROCK) have been identified, known as ROCK1 and ROCK2. It has recently been shown that in-vivo deletion of ROCK1 causes insulin resistance, whereas whether ROCK2 has a role in regulation of insulin sensitivity is unknown. In the current study, we investigated the physiological role of ROCK2 in the regulation of whole body insulin sensitivity in mice with heterozygous ROCK2 deficiency (ROCK2 +/-). ROCK2 +/- mice showed increased glucose tolerance and whole body insulin sensitivity compared to their wild-type littermates. Increased whole body insulin sensitivity in ROCK2 +/- mice was associated with increased activation of the insulin signaling in skeletal muscles and adipose tissues. To explore the mechanism of increased peripheral insulin sensitivity in ROCK2 +/- mice, we studied PPARγ and adiponectin signaling. We found selective upregulation of PPARγ and adiponectin signaling in skeletal muscles, whereas PPAR gamma levels were downregulated in adipose tissues of ROCK2 +/- mice. These findings suggest that partial ROCK2 deficiency increases insulin sensitivity in vivo through upregulation of PPARγ selectively in skeletal muscles. This suggests that ROCK2 is a potential therapeutic target in the development of new drugs for type 2 diabetes.
40
Castelo, Rueda Maria Paulina. "The role of mitochondria in reduced penetrance of heterozygous Parkin mutations". Doctoral thesis, Università degli studi di Trento, 2021. http://hdl.handle.net/11572/319705.
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Parkinson´s Disease (PD) is the most common neurodegenerative movement disorder, estimated to affect up to 2% of the population over 65 years of age (Lin et al., 2019; Santos et al., 2019). Parkin (PRKN) mutations are the most common known cause of autosomal recessive early-onset PD, accounting for up to 77% of cases with an age of onset ≤20 years (Lucking et al., 2000), and parkin dysfunction represents a risk factor for sporadic PD (Dawson & Dawson, 2014). Parkin variants have been identified in numerous families with different genetic backgrounds (Hedrich et al., 2004) and include more than 170 mutations consisting of copy number variations (deletions or multiplications of exons), small deletions/insertions, as well as single nucleotide polymorphisms (missense, nonsense, or splice site variations) (Corti et al., 2011). Importantly, a large number of patients carry exon rearrangements that result in protein truncation (Hedrich et al., 2001). Parkin is an E3 ubiquitin ligase, mostly known for its role in facilitating the selective clearance of dysfunctional mitochondria (mitophagy), and for its involvement in several other cellular processes like mitochondrial biogenesis, free radical metabolism, and inflammation (Celardo et al., 2014). Homozygous or compound-heterozygous mutations in the Parkin gene result in highly penetrant symptom expression, while heterozygous mutations have been predicted to predispose to disease symptoms with highly reduced penetrance (Huttenlocher et al., 2015; Weissbach et al., 2017). The presence of heterozygous Parkin mutations is one of the reported potential genetic risk factors for PD; (Huttenlocher et al., 2015; Klein et al., 2007). Considering the reported frequency of heterozygous mutations in the population (up to 3%), it is essential to have better estimates of the penetrance of these variants, and to investigate which risk markers manifest in carriers and are potentially useful for identifying those individuals at greater risk of neurodegeneration later in life. Furthermore, it is of great importance to test the causal link between heterozygous pathogenic mutations in Parkin and expressivity of molecular phenotypes in cellular models derived from mutation carriers. This was addressed in this thesis by (1) identifying Parkin mutation carriers in the population-based CHRIS study and characterizing them for the presence of PD risk markers; and (2) by evaluating mitochondrial integrity, including mitochondrial DNA variation and mitochondrial function, in diverse cellular models of heterozygous Parkin mutation carriers. I was able to show that heterozygous Parkin mutation carriers in the general population have increased occurrence of diabetes and decreased heart rate. Moreover, in a subset of individuals, I have identified an altered molecular phenotype, characterized by disparities at the level of mtDNA integrity and mitochondrial function in blood and two different cellular models derived from the mutation carriers. To adequately understand individual disease conversion, there is a need for more longitudinal studies with putatively healthy individuals carrying Parkin mutations and more in-depth clinical phenotyping.
41
Harmel, Eva-Maria Sophia. "Klinisches Erscheinungsbild und funktionelle Charakterisierung eines Patienten mit einer heterozygoten Exon 6 Deletion im IGF1R". Doctoral thesis, Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-163923.
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Hintergrund: Der Insulin-like growth factor receptor (IGF1R) spielt eine zentrale Rolle bei Wachstumsprozessen. Heterozygote IGF1R-Mutationen führen durch eine partielle IGF1-Resistenz zu Kleinwuchs.
Methoden: Auxologische und endokrinologische Daten des Patienten wurden erhoben. Anhand von Fibroblasten wurde die IGF1R-Deletion charakterisiert und die Auswirkungen auf die mRNA- und Protein-Expression sowie die Signaltransduktion untersucht.
Ergebnisse: Der Junge, der eine heterozygote Exon 6 Deletion im IGF1R – durch Alu-Rekombination verursacht – und eine heterozygote SHOX-Variante (p.Met240Ile) in seinem Genom vereint, kam ‚appropriate for gestational age‘ zur Welt, entwickelte aber postnatal eine Wachstumsretardierung. Die Endokrinologischen Daten waren unauffällig. Der Patient zeigt keine Stigmata, die bei anderen IGF1- oder SHOX-Mutationsträgern beschrieben wurden. Durch Nonsense-Mediated mRNA Decay kommt es zu einer Dosisreduktion der IGF1-Rezeptoren und einer entsprechenden verminderten Aktivierung der Rezeptoren, nicht aber des Signalwegs.
Zusammenfassung: Der Patient trägt eine bisher unbeschrieben heterozygote IGF1R-Deletion, die zu Kleinwuchs führt. Ursächlich dafür ist eine durch die Mutation verursachte Dosisreduktion der IGF1-Rezeptoren.
42
Grim, Travis. "Synthetic cannabinoids versus delta-9-tetrahydrocannabinol: abuse-related consequences of enhanced efficacy at the cannabinoid 1 receptor". VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/4039.
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In the past ten years, synthetic cannabinoids (SC) have emerged as drugs of abuse. Unlike D9-tetrahydrocannabinol (THC), many SCs are associated with serious health complications and death. One way in which THC and SCs differ lies with their enhanced potency and efficacy at the CB1 receptor. No current methods exist to measure efficacy at the CB1 receptor in vivo, and the abuse-related properties of SC cannabinoids are not well explored. Here, we utilized CB1 wild type (WT), heterozygous (HET), and knockout (KO) mice. By employing CB1 ligands which differ in efficacy we have developed a method to explore the relationship between efficacy and the ability to produce cannabimimetic (catalepsy, hypothermia, and antinociception) effects when CB1 expression was reduced by half. Additionally, the intracranial self-stimulation procedure (ICSS) was utilized to investigate the effects of enhanced efficacy at CB1 upon reward processes using representative SC CP55,940. As predicted, the potency shift between WT and HET mice inversely correlated with the efficacy of the test drug for both hypothermia and antinociception, but not catalepsy. This efficacy stratification was correlated with the agonist-stimulated [35S]GTPgS binding assay, demonstrating this model as an effective tool to ascertain in vivo efficacy differences at CB1. In ICSS, CP55,940 elicited only rate-decreasing effects acutely, although tolerance developed following repeated dosing, with no evidence for spontaneous or rimonabant-precipitated withdrawal. Together, these data indicate that highly efficacious cannabinoid ligands require few receptors to produce cannabimimetic effects, and that the model provides an effective means to quickly ascertain differences in efficacy.
43
CHEMILA, CARENCO MARGUERITE. "Mycoplasmose pulmonaire grave associee a un deficit heterozygote en facteur vii : a propos d'une observation". Aix-Marseille 2, 1989. http://www.theses.fr/1989AIX20194.
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Wu, Pei-Chi Coleman Rosalind A. "Will absence of GPAT1 improve diet-induced atherosclerosis in ApoE heterozygous mice?" Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2008. http://dc.lib.unc.edu/u?/etd,1933.
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Thesis (M.S.)--University of North Carolina at Chapel Hill, 2008.Title from electronic title page (viewed Dec. 11, 2008). "... in partial fulfillment of the requirement for the degree of Master of Science in the Department of Nutrition." Discipline: Nutrition; Department/School: Public Health.
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Wolf, Susanne. "Einfluss blutdrucksenkender Pharmaka auf die Ausbildung einer ARVC bei heterozygot plakoglobindefizienten Mäusen". Giessen VVB Laufersweiler, 2009. http://d-nb.info/996005285/04.
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Richters, Lisa Katharina [Verfasser]. "Morphologische, funktionelle und histochemische Untersuchungen zur trainingsinduzierten kardialen Adaptation heterozygoter MnSOD-Knockout-Mäuse / Lisa Katharina Richters". Köln : Deutsche Zentralbibliothek für Medizin, 2012. http://d-nb.info/1019659645/34.
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Schatz, Stephanie Verfasser], e Ania [Akademischer Betreuer] [Muntau. "X-Inaktivierung bei heterozygoten Patientinnen bezüglich X-chromosomal vererbtem Morbus Fabry / Stephanie Schatz. Betreuer: Ania Muntau". München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2012. http://d-nb.info/1027949193/34.
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Mazur, Artur, Katrin Köhler, Markus Schülke, Mandy Skunde, Mariusz Ostański e Angela Hübner. "Familial Glucocorticoid Deficiency Type 1 due to a Novel Compound Heterozygous MC2R Mutation". Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-134512.
Texto completo da fonteResumo:
Objective: Description of the clinical, biochemical and genetic features of a Polish patient with familial glucocorticoid deficiency. Methods: Detailed clinical investigation, hormonal analysis and sequencing of the coding region of the melanocortin 2 receptor (MC2R) gene in this patient. Results: We report on a 3-month-old boy with familial glucocorticoid deficiency who presented at the age of 3 months with skin hyperpigmentation, muscle weakness, mild jaundice and constipation. Hormonal analyses revealed high ACTH and TSH serum concentrations, low serum cortisol concentration along with normal blood electrolytes. On hydrocortisone supplementation, the disease symptoms disappeared and the child recovered completely. His physical and mental development progresses normally. Genetic analysis disclosed a novel compound heterozygous MC2R mutation p.Leu46fs and p.Val49Met. Conclusion: The heterozygous p.Leu46fs mutation adds to the small number of MC2R nonsense mutations and is the first frameshift mutation within the first transmembrane domain of the receptor. According to molecular modeling the Val49Met mutation results in a structural change of the first transmembrane domain and in a potential novel interaction of the transmembrane domains I and VIIDieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich
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Mazur, Artur, Katrin Köhler, Markus Schülke, Mandy Skunde, Mariusz Ostański e Angela Hübner. "Familial Glucocorticoid Deficiency Type 1 due to a Novel Compound Heterozygous MC2R Mutation". Karger, 2008. https://tud.qucosa.de/id/qucosa%3A27575.
Texto completo da fonteResumo:
Objective: Description of the clinical, biochemical and genetic features of a Polish patient with familial glucocorticoid deficiency. Methods: Detailed clinical investigation, hormonal analysis and sequencing of the coding region of the melanocortin 2 receptor (MC2R) gene in this patient. Results: We report on a 3-month-old boy with familial glucocorticoid deficiency who presented at the age of 3 months with skin hyperpigmentation, muscle weakness, mild jaundice and constipation. Hormonal analyses revealed high ACTH and TSH serum concentrations, low serum cortisol concentration along with normal blood electrolytes. On hydrocortisone supplementation, the disease symptoms disappeared and the child recovered completely. His physical and mental development progresses normally. Genetic analysis disclosed a novel compound heterozygous MC2R mutation p.Leu46fs and p.Val49Met. Conclusion: The heterozygous p.Leu46fs mutation adds to the small number of MC2R nonsense mutations and is the first frameshift mutation within the first transmembrane domain of the receptor. According to molecular modeling the Val49Met mutation results in a structural change of the first transmembrane domain and in a potential novel interaction of the transmembrane domains I and VII.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
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Khourieh, Joëlle. "Novel heterozygous STAT3 mutations clarify the molecular basis of the hyper IgE syndrome". Thesis, Sorbonne Paris Cité, 2018. https://wo.app.u-paris.fr/cgi-bin/WebObjects/TheseWeb.woa/wa/show?t=2177&f=15771.
Texto completo da fonteResumo:
À ce jour, STAT3 est le seul gène pour lequel des mutations dans les régions codantes sont à l'origine du syndrome hyper-immunoglobuline E autosomique dominant (AD-HIES). Cependant, l'étiologie génétique de 5% des individus répondant aux critères cliniques pour l'AD-HIES reste inconnue. En combinant le séquençage de l'exome entier et l'analyse de liaison génétique, nous avons identifié la première mutation hétérozygote STAT3 intronique, c.1282-89C>T, causant l'AD-HIES chez sept patients de la même famille. Cette mutation crée un nouvel exon au niveau de l'ADNc de STAT3 (D427ins17). Nous avons également identifié deux nouvelles mutations STAT3 non-sens; c.1552C>T conduisant à une protéine tronquée avec un codon stop dans le domaine de liaison de STAT3 (R518*) chez un patient souffrant de l'AD-HIES, et c.2091delT conduisant à une protéine tronquée avec un codon stop entraînant un décalage du cadre de lecture dans le domaine de transactivation de STAT3 (D698Tfs*9) chez deux apparentés atteints de la tuberculose. Dans un système de surexpression, les trois protéines STAT3 mutantes sont perte de fonction en terme de phosphorylation de la tyrosine, de liaison à l'ADN et d'activité transcriptionnelle. Dans les lymphocytes B des patients, les deux allèles non-sens ne sont pas exprimés alors que nous avons trouvé par spectrométrie de masse que l'allèle D427ins17 ne représente que 5 à 20% du STAT3 total dans les cellules du patient. L'activation des leucocytes du patient a démontré une faible réponse aux cytokines STAT3-dépendantes, comme d'autres patients avec l'AD-HIES. Dans un système de surexpression, nous avons montré que les allèles D427ins17 et D698Tfs*9 sont également dominants-négatifs, alors que l'allèle R518* est neutre. Ce travail démontre l'importance du séquençage des introns dans l'établissement du diagnostic génétique pour l'AD-HIES. De plus, l'étude de l'allèle D427ins17 suggère que les mutations provoquant l'AD-HIES peuvent exercer un effet dominant-négatif même lorsqu'elles sont exprimées à des niveaux significativement inférieurs à ceux de la protéine de type sauvage. En revanche, l'étude de l'allèle R518* suggère l'haploinsuffisance comme étant un autre mécanisme susceptible d'entraîner l'AD-HIES; cependant, l'identification et la caractérisation d'un plus grand nombre de mutations non-sens sont nécessaires avant de pouvoir tirer des conclusions définitivesTo date STAT3 is the only gene in which variants in coding regions are known to cause Autosomal Dominant Hyper-Immunoglobulin E Syndrome (AD-HIES). Yet, the genetic etiology of 5% of individuals meeting the clinical criteria for AD-HIES remains unknown. Combining whole exome sequencing and genetic linkage analysis, we identified the first deep intronic heterozygous STAT3 mutation, c.1282-89C>T, causing AD-HIES in seven relatives. This mutation creates a new exon in the STAT3 cDNA (D427ins17). We also identified two novel nonsense STAT3 mutation; c.1552C>T leading to a truncated protein with a stop codon in the STAT3 linker domain (R518*) in a patient with AD-HIES, and c.2091delT leading to a truncated protein with a stop codon with a frameshift in STAT3 transactivation domain (D698Tfs*9) in two relatives with tuberculosis. Upon over-expression, the three mutant STAT3 proteins are loss of function in terms of tyrosine phosphorylation, DNA-binding, and transcriptional activity. In patient's B cells, R518* and D698Tfs*9 alleles are not expressed whereas we found by mass spectrometry that the D427ins17 allele only represents 5 to 20% of total STAT3 in the patient's cells. Activation of patient's leucocytes demonstrated a poor respond to STAT3-dependent cytokines, like other patients with AD-HIES. Upon overexpression, we show that D427ins17 and D698Tfs*9 are equally dominant-negative alleles, whereas R518* allele is neutral. This work emphasis the importance of intron sequencing in the establishment of genetic diagnostics in AD-HIES. Moreover, the study of the D427ins17 allele suggests that AD-HIES-causing mutations can exert their negative-dominance even when expressed at significantly lower levels than the wild-type protein. On the other hand, the study of R518* allele shed the light on haploinsufficiency as another possible mechanism causing AD-HIES; however, the identification and characterization of more nonsense mutations is necessary before drawing any firm conclusions