ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation. (1/1094)

Investigation of a critical region for an X-linked mental retardation (XLMR) locus led us to identify a novel Aristaless related homeobox gene (ARX ). Inherited and de novo ARX mutations, including missense mutations and in frame duplications/insertions leading to expansions of polyalanine tracts in ARX, were found in nine familial and one sporadic case of MR. In contrast to other genes involved in XLMR, ARX expression is specific to the telencephalon and ventral thalamus. Notably there is an absence of expression in the cerebellum throughout development and also in adult. The absence of detectable brain malformations in patients suggests that ARX may have an essential role, in mature neurons, required for the development of cognitive abilities.  (+info)

Chromosome abnormalities in sperm from infertile men with asthenoteratozoospermia. (2/1094)

Research over the past few years has clearly demonstrated that infertile men have an increased frequency of chromosome abnormalities in their sperm. These studies have been further corroborated by an increased frequency of chromosome abnormalities in newborns and fetuses from pregnancies established by intracytoplasmic sperm injection. Most studies have considered men with any type of infertility. However, it is possible that some types of infertility have an increased risk of sperm chromosome abnormalities, whereas others do not. We studied 10 men with a specific type of infertility, asthenozoospermia (poor motility), by multicolor fluorescence in situ hybridization analysis to determine whether they had an increased frequency of disomy for chromosomes 13, 21, XX, YY, and XY, as well as diploidy. The patients ranged in age from 28 to 42 yr (mean 34.1 yr); they were compared with 18 normal control donors whose ages ranged from 23 to 58 yr (mean 35.6 yr). A total of 201 416 sperm were analyzed in the men with asthenozoospermia, with a minimum of 10 000 sperm analyzed per chromosome probe per donor. There was a significant increase in the frequency of disomy in men with asthenozoospermia compared with controls for chromosomes 13 and XX. Thus, this study indicates that infertile men with poorly motile sperm but normal concentration have a significantly increased frequency of sperm chromosome abnormalities.  (+info)

MOUSE (Mitochondrial and Other Useful SEquences) a compilation of population genetic markers. (3/1094)

Mitochondrial and Other Useful SEquences (MOUSE) is an integrated and comprehensive compilation of mtDNA from hypervariable regions I and II and of the low recombining nuclear loci Xq13.3 from about 11 200 humans and great apes, whose geographic and if applicable, linguistic classification is stored with their aligned sequences and publication details. The goal is to provide population geneticists and genetic epidemiologists with a comprehensive and user friendly repository of sequences and population information that is usually dispersed in a variety of other sources. AVAILABILITY: http://www.gen-epi.de/mouse. SUPPLEMENTARY INFORMATION: Documentation and detailed information on population subgroups is available on the homepage: http://www.gen-epi.de/mouse  (+info)

Bipolar disorder susceptibility region on Xq24-q27.1 in Finnish families. (4/1094)

Bipolar disorder (BPD) is a common disorder characterized by episodes of mania, hypomania and depression. The genetic background of BPD remains undefined, although several putative loci predisposing to BPD have been identified. We have earlier reported significant evidence of linkage for BPD to chromosome Xq24-q27.1 in an extended pedigree from the late settlement region of the genetically isolated population of Finland. Further, we established a distinct chromosomal haplotype covering a 19 cM region on Xq24-q27.1 co-segregating with the disorder. Here, we have further analyzed this X-chromosomal region using a denser marker map and monitored X-chromosomal haplotypes in a study sample of 41 Finnish bipolar families. Only a fraction of the families provided any evidence of linkage to this region, suggesting that a relatively rare gene predisposing to BPD is enriched in this linked pedigree. The genome-wide scan for BPD predisposing loci in this large pedigree indicated that this particular X-chromosomal region provides the best evidence of linkage genome-wide, suggesting an X-chromosomal gene with a major role for the genetic predisposition of BPD in this family.  (+info)

Sperm aneuploidy rates in younger and older men. (5/1094)

BACKGROUND: In order to assess the possible risk of chromosomal abnormalities in offspring from older fathers, we investigated the effects of age on the frequency of chromosomal aneuploidy rates of human sperm. METHODS AND RESULTS: Semen samples were collected from 15 men aged <30 years (24.8 +/- 2.4 years) and from eight men aged >60 years (65.3 +/- 3.9 years) from the general population. No significant differences in ejaculate volume, sperm concentration and sperm morphology were found, whereas sperm motility was significantly lower in older men (P = 0.002). For the hormone values, only FSH was significantly elevated in the older men (P = 0.004). Multicolour fluorescence in-situ hybridization was used to determine the aneuploidy frequencies of two autosomes (9 and 18); and of both sex chromosomes using directly labelled satellite DNA probes on decondensed sperm nuclei. A minimum of 8000 sperm per donor and >330 000 sperm in total were evaluated. The disomy rates per analysed chromosomes were 0.1-2.3% in younger men and 0.1-1.8% in older men. The aneuploidy rate determined for both sex chromosomes and for the autosomes 9 and 18 were not significantly different between the age groups. CONCLUSIONS: The results suggest that men of advanced age still wanting to become fathers do not have a significantly higher risk of procreating offspring with chromosomal abnormalities compared with younger men.  (+info)

Meta-analysis of genotype-phenotype correlation in X-linked Alport syndrome: impact on clinical counselling. (6/1094)

BACKGROUND: Alport syndrome (AS) is a hereditary nephropathy characterized by progressive renal failure, hearing loss and ocular lesions. Numerous mutations of the COL4A5 gene encoding the alpha 5-chain of type IV collagen have been described, establishing the molecular cause of AS. The goal of the present study was to identify the genotype-phenotype correlations that are helpful in clinical counseling. COL4A5-mutations (n=267) in males were analysed including 23 German Alport families. METHODS: Exons of the COL4A5 gene were PCR-amplified and screened by Southern blot, direct sequencing or denaturing gradient gel electrophoresis. Phenotypes were obtained by questionnaires or extracted from 44 publications in the literature. Data were analysed by Kaplan-Meier statistics, chi(2) and Kruskal-Wallis tests. RESULTS: Genotype-phenotype data for 23 German Alport families are reported. Analysis of these data and of mutations published in the literature showed the type of mutation being a significant predictor of end-stage renal failure (ESRF) age. The patients' renal phenotypes could be grouped into three cohorts: (1) large rearrangements, frame shift, nonsense, and splice donor mutations had a mean ESRF age of 19.8+/-5.7 years; (2) non-glycine- or 3' glycine-missense mutations, in-frame deletions/insertions and splice acceptor mutations had a mean ESRF age of 25.7+/-7.2 years and fewer extrarenal symptoms; (3) 5' glycine substitutions had an even later onset of ESRF at 30.1+/-7.2 years. Glycine-substitutions occurred less commonly de novo than all other mutations (5.5% vs 13.9%). However, due to the evolutionary advantage of their moderate phenotype, they were the most common mutations. The intrafamilial phenotype of an individual mutation was found to be very consistent with regards to the manifestation of deafness, lenticonus and the time point of onset of ESRF. CONCLUSIONS: Knowledge of the mutation adds significant information about the progress of renal and extrarenal disease in males with X-linked AS. We suggest that the considerable prognostic relevance of a patient's genotype should be included in the classification of the Alport phenotype.  (+info)

Low frequency of MECP2 mutations in mentally retarded males. (7/1094)

A high frequency of mutations in the methyl CpG-binding protein 2 (MECP2) gene has recently been reported in males with nonspecific X-linked mental retardation. The results of this previous study suggested that the frequency of MECP2 mutations in the mentally retarded population was comparable to that of CGG expansions in FMR1. In view of these data, we performed MECP2 mutation analysis in a cohort of 475 mentally retarded males who were negative for FMR1 CGG repeat expansion. Five novel changes, detected in seven patients, were predicted to change the MECP2 coding sequence. Except for one, these changes were not found in a control population. While this result appeared to suggest a high mutation rate, this conclusion was not supported by segregation studies. Indeed, three of the five changes could be traced in unaffected male family members. For another change, segregation analysis in the family was not possible. Only one mutation, a frameshift created by a deletion of two bases, was found to be de novo. This study clearly shows the importance of segregation analysis for low frequency mutations, in order to distinguish them from rare polymorphisms. The true frequency of MECP2 mutations in the mentally retarded has probably been overestimated. Based on our data, the frequency of MECP2 mutations in mentally retarded males is 0.2% (1/475).  (+info)

Species-specific subcellular localization of RPGR and RPGRIP isoforms: implications for the phenotypic variability of congenital retinopathies among species. (8/1094)

The retinitis pigmentosa GTPase regulator (RPGR) is encoded by the X-linked RP3 locus, which upon genetic lesions leads to neurodegeneration of photoreceptors and blindness. The findings that RPGR specifically and directly interacts in vivo and in vitro with retina-specific RPGR-interacting protein 1 (RPGRIP) and that human mutations in RPGR uncouple its interaction with RPGRIP provided the first clue for the retina-specific pathogenesis of X-linked RP3. Recently, mutations in RPGRIP were found to lead to the retinal dystrophy, Leber congenital amaurosis. However, mouse models null for RPGR had, surprisingly, a very mild phenotype compared with those observed in XlRP3-affected humans and dogs. Moreover, recent reports are seemingly in disagreement on the localization of RPGR and RPGRIP in photoreceptors. These discrepancies were compounded with the finding of RPGR mutations leading exclusively to X-linked cone dystrophy. To resolve these discrepancies and to gain further insight into the pathology associated with RPGR- and RPGRIP-allied retinopathies, we now show, using several isoform-specific antibodies, that RPGR and RPGRIP isoforms are distributed and co-localized at restricted foci throughout the outer segments of human and bovine, but not mice rod photoreceptors. In humans, they also localize in cone outer segments. RPGRIP is also expressed in other neurons such as amacrine cells. Thus, the data lend support to the existence of species-specific subcellular processes governing the function and/or organization of the photoreceptor outer segment as reflected by the species-specific localization of RPGR and RPGRIP protein isoforms in this compartment, and provide a rationale for the disparity of phenotypes among species and in the human.  (+info)

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