Academic literature on the topic 'X linked mental retardation'

In order to determine the proportion of MR due to fragile X, CGG repeat analysis was carried out on DNA from 723 mentally retarded patients in S.E. Scotland. This resulted in the identification of 8 new cases of fragile X syndrome (˜1% of the total number of referrals for developmental delay). This developmentally delayed cohort was also compared to normal and high IQ cohorts to address the possibility of a relationship between CGG repeat number and IQ variation in the general population. Two complicated prenatal diagnostic cases were studied in detail to answer important practical questions concerning the nature and timing of repeat expansion. Well over 100 other XLMR conditions have been described, of which approximately 50% have been regionally mapped. Some of these are non-specific forms of XLMR in which MR is the only manifestation; others are XLMR syndromes with a characteristic and well defined phenotype. A family with non-specific XLMR is described in which the proband presented as a non dysmorphic male with unexplained MR, for exclusion of fragile X syndrome. He had a CGG allele in the normal range and the MR segregating in the family was shown not to be linked to FMRI. Subsequent analysis of polymorphic X-linked markers showed linkage to Xq21. A new XLMR syndrome is represented by a large family with severe MR and spastic diplegia which was previously thought to be MASA syndrome, a condition caused by mutations in the LICAM gene in distal Xq28. Negative LOD scores with Xq28 markers led to a search for linkage to other regions; this was found in Xp22 where several other XLMR loci are located, although the clinical features of this family differ from those of other XLMR syndromes and conditions in Xp22.

The Indonesian archipelago comprises more than 17,000 islands, inhabited by ~200 million people constituting more than 350 recognizable ethnic and tribal groups which can be classified into two broad ethno-linguistic groups [the Austronesian (AN) and non-Austronesian (NAN) speaking peoples] and 3 physical anthropology groups (Deutero Malay, Proto Malay and Papuan). The origins of these groups are of considerable anthropological interest. The anthropology of Indonesia is extremely complex and still controversial. The present populations of Indonesia show very great diversity. The data presented below result from an investigation of the Fragile X A syndrome and the size and distribution of alleles at fragile sites on the X chromosome among Javanese males with developmental disability (DD) and unselected males from 10 major Indonesian ethnic groups. The Fragile X syndrome is caused by expansion of a CGG trinucleotide repeat array in the 5' untranslated region of the FMR-1 gene at Xq27.3. Normal X chromosomes have between 6-54 CGG trinucleotide repeats, whereas premutation alleles have 55-230 and full mutation alleles more than 230 repeats. In a study of predominantly Caucasian males with intellectual disability, the prevalence of Fragile X syndrome is estimated to be approximately 1:4,000. FRAXE mental retardation syndrome is caused by an expansion of a GCC trinucleotide repeat in the 5'UTR of FMR2 gene located 600 kb telomeric to FMR1. The prevalence of FMR2 is 1-2 per 100,000 live births. FMR2 common alleles consist of 11-30 GGC repeats; intermediate alleles between 31-60 GCC repeats; premutation alleles with 61-200 repeats and full mutation alleles have over 200 repeats with attendant methylation of the repeat array The first Indonesian screening program aimed at determining the presence and prevalence of fragile XA syndrome among individuals with mild DD (IQ above 50) from special schools (N=205) and isolated areas (N=50) of Java was undertaken in 1994-1996 by cytogenetic and molecular studies. In this first study 4 fragile X positive children were found among 255 males with DD. The estimated prevalence of fragile-X in males with mild DD from special schools was 1.95% (5/205) and the overall prevalence was 1.57% (4/255). The number of trinucleotide repeats in the 5' untranslated regions of the FMR1 and FMR2 genes were determined by PCR in 254 Fragile XA-negative Javanese male children with DD. The distribution of FMR1 and FMR2 trinucleotide repeat alleles was found to be significantly different in the Indonesian population with DD compared to that in equivalent Caucasian populations. The trimodal distribution of Indonesian FMR1 alleles (29, 30 and 36 repeats) is largely in agreement with findings from other Asian populations). This provides supportive evidence that the origin of Indonesians could be the same as that of the Chinese and Japanese. Sequence analysis was performed on the trinucleotide repeat arrays of the 27 individuals' FMR1 alleles in the 'grey zone' (35-52 repeats). The identification of 16 unrelated individuals with a (CGG)36 allele that also contains a (CGG)6 segment [(CGG)9AGG(CGG)9AGG(CGG)6 AGG(CGG)9 or 9A9A6A9 pattern] is in agreement with earlier observations in the Japanese population. It is proposed that this FMR1 array pattern may be specific for Asian populations and that Javanese and Japanese populations may have arisen from a single progenitor population. The presence of pure 25, 33 and 34 CGGs in FMR1 alleles with 36, 44 and 45 repeats respectively, suggests that these may represent alleles at high risk for instability and may therefore be at early stages of expansion to a premutation. The lack of the characteristic (CGG)6 in all three alleles with ?? 25 pure CGG arrays suggests that the most common Asian 36 repeat allele is not predisposed to slippage expansion. Seven of the 8 alleles with 36 CGG repeats could be sequenced. Seven of 36 CGG repeats FMR1 alleles from the Hiri population has been sequenced and 4 alleles indicated 9A9A6A9 pattern, 1 sample with 10A25 pattern Two of the remaining alleles showed 12A6A6A9 structure, which consisted of a tandem duplication of the (CGG)6 segment. The presence of a tandem duplication of (CGG)6 segments has never been reported in any other population. The other major findings of this study are that FRAXE syndrome is a rare cause of developmental disability in this predominantly-Javanese population. The most common FMR2 (GCC)20 allele in this selected Asian population is significantly longer than that previously reported for Caucasian populations. There was a weak correlation between the overall length of the FMR1 and FMR2 repeat arrays within the normal range (Spearman's Rank Correlation = 0.130, p-value=0.042) in the Indonesian population, which have been no previous associations reported for alleles within the normal range. One approach to studying the origins of the human populations is to study the genetic structure of polymorphic alleles such as those at the FMR1 locus and its linked microsatellite markers DXS548 and FRAXAC1. Length polymorphisms of the FMR1 gene (CGG)n repeat array, DXS548 and FRAXAC1 were studied in a total of 1,008 unselected males from 10 different Indonesian ethnic groups. FMR1 alleles were identified ranging from 8 to 57 CGG repeats. The most common CGG repeat allele was 29 (45.6%) followed by 30 (27.4%) and 36 repeats (8.0%). One hundred and forty four grey zone (3-52 CGG) alleles were found in the study population. Four people of the same ethnic group from an isolated island in Eastern Indonesia (Hiri, Ternate), a representative of the NAN ethnolinguistic group, had CGG repeat lengths of 55-57. The prevalence of these alleles is estimated to be 3.3% (4/120) in the population of Hiri or 0.4% (4/1008) of whole Indonesian population. Thirteen different alleles were found at the DXS548 locus, of which allele numbers 7 [194 bp] (44.1%), 6.5 [195bp] (43.5%) and 6 [196bp] (7.5%) are the most common. Seven rare alleles, some of which have not been previously found in Asian peoples were also identified (190, 191,192, 193, 197,198, 199, 202, 204 and 206) and accounted for 3.9% of the total. The odd number alleles were dominantly found in this study whereas almost none found in Caucasian. The finding of many "odd numbered" alleles DXS548 has never been found in other Asian population and has only been documented extremely rarely in Caucasians and Africans. Five different alleles of FRAXAC1 identified with alleles D [106 bp] (62.2%) and C [108bp] (35.6%) accounting for 97.8% of FRAXAC1 alleles in the population. Three rare alleles (104, 110, 112 bp = 2.2%) were identified that have not been previously found in other Asian populations (1-3). There is a striking linkage disequilibrium of FMR1 alleles with FRAXAC1 (p=0.0001), 88% of 29 (CGG)n repeats alleles associated with FRAXAC1 allele D (106bp) versus only 17% with the 30 (CGG)n repeat alleles, which is in agreement with other studies. The value of D' was calculated to be 0.7. The longer alleles of both DXS548 and FRAXAC1 were found mostly in the NAN ethnolinguistic group. Moreover the Irian Jaya people also showed a higher percentage of people with 30 CGG repeats and the 108 bp FRAXAC1. The Eastern Indonesian NAN groups demonstrate a different genetic background probably due to the contribution of Melanesian peoples. The Analysis of Molecular Variance (AMOVA) identified that the vast majority of genetic diversity occurs within, rather than between, ethnic groups. These data are consistent with a model where there is sufficient migration (~20 per generation) between populations to minimise differentiation of population through genetic drift. The results obtained are consistent with three clusters of populations that share similar allele frequencies at the fragile X locus. The most clearly defined cluster is based in the east of Indonesia and includes the two Irian populations, Minahasans and Hiri. A surprising finding was that the Minahasan who are Deutero-Malay in origin and physical appearance are genetically closer to the Irianese. This may reflect the admixture of Melanesian alleles or other eastern Indonesian alleles as a result of their geographic location in that part of Indonesia. The second major cluster is largely based in the west of the country and is composed of the following Deutero-Malay populations; Javanese, Balinese, Acehnese but which also includes people from Ternate (not including those from Hiri). Using Delta Mu and Nei's genetic distance for FMR1 locus in this study the Javanese were shown to have the closest distance to Balinese which is consistent with anthropological data and with published data. The third group is a "western and central" group composed of Bimanese, Dayak and Sundanese who share some features of the western and eastern clusters but mostly resemble the western Indonesian populations. Bima is located in the lesser Sunda in between west Indonesia and east Indonesia. The Bimanese are of mixed Deutero & Proto Malay origin that is consistent with their geographic location. The Bataks are distinctive and sit somewhat apart in this scheme. In this study, Bataks were found not to resemble the other Proto-Malay group studied (the Dayak). The Dayaks were found to have fewer alleles than the Bataks at FRAXAC1 and DXS548. In all four methods of calculating genetic distance Bataks showed a large genetic distance to almost all other ethnic groups. There are differences in allele frequency between east and west Indonesia as well as other Asian nations, but the genetic similarities between these groups are also very impressive. The findings from this study are consistent with other genetic anthropological evidence that the people of Indonesia have the same origin as North-east Asian groups. This model is referred to as the "express train from Taiwan" in which the Austronesian speakers are proposed to have radiated from Taiwan bringing the Malayo-Polynesian language group to the Philippines, Borneo and Sulawesi around 5000-4500 B.P.E. However Richards et al.(1998) have used the diversity in the mtDNA D Loop to propose an alternative to the "express train" model. The "two train7quot; model proposes that the Austronesian languages originated within eastern Indonesia during the Pleistocene era and spread through Melanesia and into the remote Pacific within the past 6,000 years. Unfortunately the high migration rates between population groups that were demonstrated in this thesis and the known migration patterns of populations through Indonesia preclude determining whether the observed allelic heterogeneity is a function of the original population or due to the admixture of several gene pools in more recent times.

Mental retardation (MR) affects 23% of the population; those due to X linked mutations commonly result in moderate to severe MR. The OPHN1 gene (Ophn1 in mice) has been implicated in X linked mental retardation (XLMR) and encodes the RhoGAP protein, oligophrenin 1. Loss of function mutations alter Rho GTPase dependent signalling pathways and result in altered actin cytoskeleton dynamics which are important in dendritic spine structure, the site of neurotransmission. Here, using electrophysiological recordings combined with intracellular staining techniques and dendritic morphological analysis, I characterise synaptic (dys)function in neocortical and hippocampal neurons from the Ophn1 mouse model of MR. This study demonstrates an excitatory synaptic deficit in neocortical neurons combined with region specific changes in dendritic spine morphology. Inhibitory transmission was normal in both neocortical and hippocampal neurons. Kainate induced gamma oscillations were unaltered whereas spontaneous oscillations were reduced which lead to changes in synaptic function in CA3. Morphometric analysis showed ventriculomegaly in Ophn1 deficient mice that was associated with reduced cortical thickness. This study shows the loss of several previously reported phenotypes, including, altered inhibitory transmission, gamma oscillations and vesicle dynamics. Their loss, but preservation of morphological deficits, suggests that the model may be susceptible to genetic drift.

Twenty-one genes are known that when mutated cause non-syndromic X-linked mental retardation (NS-XLMR), a condition in which learning disability is the only consistent clinical feature among affected individuals. The principal aim of this project was to identify further NS-XLMR genes. To achieve this aim we characterized X chromosomal breakpoints in rare patients with apparently balanced X;autosome translocations and learning disability to identify disrupted candidate NS-XLMR genes. In patient LPW, a female with a translocation involving chromosomes X and 8, we identified a small 650 kb duplication at the X chromosome breakpoint that was likely to be responsible for the patient’s learning disability. In patient AGO819, the CLCN5 gene was found to be disrupted by the X chromosomal breakpoint. As CLCN5 is a gene mutated in a familial renal disease not associated with learning disability then expression analysis of genes adjacent to CLCN5 was performed. A position effect disrupting the expression of a neighbouring gene, CCNB3, was detected indicating that the expression of one or more genes surrounding the X chromosome breakpoint was disrupted. One of these genes, KIAA1202, has recently been reported to be mutated in familial learning disability. In a third patient with a balanced translocation, KD, no gene was found disrupted by the X chromosome breakpoint and further analysis indicated that this patient’s learning disability was likely to be related to abnormalities at the autosomal breakpoint. The project was concluded by characterizing two mutations identified in DLG3. We proved that the genomic mutations disrupted splicing of DLG3 at the mRNA level, confirming that the mutations were likely to be disease-causing in the two families.

Mental retardation (MR) is a handicap with severe implications not only for thosethat suffer from this disability, but also for their families, society and the welfaresystems which support them. A large proportion of these individuals are afflictedwith the X-linked form of the condition. To date a total of 87 genes have beenimplicated in the pathogenesis of X-linked mental retardation (XLMR).

The primary objective of the studies presented here was to identify candidate genes for nonsyndromic X-linked mental retardation (NS-XLMR) in Xp11.2 by molecular characterisation of the Xp11.2 breakpoints in five rare female individuals with balanced X;autosome translocations and mental retardation. The hypothesis underlying this positional cloning strategy was that genes disrupted by the X chromosome breakpoints are candidate genes for NS-XLMR. Five Xp11.2 and three autosomal translocation breakpoints were mapped by fluorescence in situ hybridisation (FISH) using large insert genomic clones generated by the Human Genome Project as probes. In silico analysis of genomic sequences at the X breakpoint loci was used to identify genes potentially disrupted by the translocations. In collaboration with Dr Vera Kalscheuer’s group in Berlin, a putative diacylglycerol kinase XM_066534 was found to be disrupted by a t(X;22), and its involvement in NS-XLMR evaluated. Restriction mapping by southern blot hybridisation analysis was undertaken to fine map the X breakpoints of two translocations, and RT-PCR analysis used to investigate expression of genes at the X breakpoint loci in translocation cell lines. One t(X;16) was found to disrupt expression of the zinc finger gene ZNF81. This is the second example of a balanced X;autosome translocation associated with mental retardation which disrupts this gene, providing further evidence that mutations in ZNF81 cause mental retardation. The X breakpoint of a second t(X;16) was localised to a 9 kb interval between two partial cDNAs. Further work on these sequences led to the cloning and characterisation of two novel genes expressed in brain, WNK3, a putative protein kinase, and CXorf17 and its mouse ortholog, orf34. Characterisation of CXorf17 and orf34 facilitated the identification of a novel, chordate-specific gene family which encodes several putative transmembrane proteins that have no sequence homology to any previously annotated proteins, known functional domains or sequence motifs.

Mental retardation is the most common brain disease. One of the first genes identified in X-linked mental retardation (XLMR) was the OPHN-1 gene. Mutation of this gene has been described in patients with moderate to severe cognitive impairments. MR is characterized by reduced cognitive function with or without other clinical features, thus providing a direct approach to study the neurobiology of cognition and pathogenesis of MR. I propose in this thesis to clarify the underlying mechanisms responsible for the learning impairments. My first approach was to investigate the functioning of a neuronal population using extracellular recording of fast oscillations which are thought to underlie higher cognitive performance. I showed that \(Ophn-1\) null mice displayed weaker gamma oscillations. Thereafter, Investigation of the synaptic properties of CA3 pyramidal neurons using the patch-clamp technique has been undertaken. I have shown reduced inputs of excitatory and inhibitory neurotransmission to CA3 pyramidal neurons accompanied with reduced frequency dependent facilitation of the inhibitory neurotransmission at 33Hz. Finally, a reduction in readily releasable pool size in inhibitory synapses of CA3 area was unravelled. This defect explained the reduction of frequency of sIPSCs and consequently the reduction in gamma oscillations power in Ophn-1\(^{-/y}\) slices.

The paper presents the design, construction, validation and testing of a Haptic Guidance Device whose aim is to provide dynamic assistance while performing manual activities such as drawing, hatching and cutting. A commercial phantom haptic device was modified by adding a pantograph mechanism in order to increase the haptic working area. The force feedback workspace provided by the phantom device is quite limited, 160 W × 120 H mm. This workspace sometimes is not enough to reproduce manual tasks in a large-scale area as is often required in several educational activities (e.g. sketching, hatching and cutting tasks). In this paper is evaluated a low cost solution for increasing the haptic working area provided by the phantom device. The pantograph mechanism has been linked with the haptic device in order to increase the working area in a 2:1 scale. The users hand moves a pen linked to the device through 2D predefined shapes in which the pens position have been tracked in 2D coordinates at 25 kHz in order to record all the data for the posterior analysis. The haptic guidance device is also equipped with a cutting system using hot wire for physically producing the drawn shape as a piece of polystyrene foam. The haptic guidance device has been tested by people with specific disorders affecting coordination such as Down syndrome and mental retardation under the supervision of their teachers and care assistants. The results of the study prove that higher performance levels can be achieved while performing manual tasks as sketching, hatching and cutting operation using the haptic guidance device.