Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The distal part of the human dystrophin gene is characterised by particular features and seems to play an important functional role. Additionally in recent years several data have implicated minor mutations in this gene region in some patients with mental retardation (MR). In order to screen for pathogenic mutations at the distal part of the human dystrophin gene we have used single-strand conformation analysis of products amplified by polymerase chain reaction (PCR-SSCA) in 35 unrelated male Greek DMD/BMD patients with no detectable deletions. Seven patients also had severe mental retardation. Direct sequencing of samples demonstrating a shift of SSCA mobility revealed six different and pathogenic minor changes, five in DMD and one in a BMD patient. Four of the mutations were found in DMD patients with severe MR. Three of these mutations were localised in exon 66, which presents an interesting similarity with part of the 3' end of the genome of eastern equine encephalomyelitis virus (EEEV). The present data from Greek DMD/BMD patients give further information about the phenotypic effects consequent on mutations in exons at the distal part of the human dystrophin gene.
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PMID:Screening for minor changes in the distal part of the human dystrophin gene in Greek DMD/BMD patients. 1019 1

The clinical and molecular features of 25 Duchenne (DMD), two intermediate (D/BMD) and three Becker (BMD) muscular dystrophy patients from 26 unrelated families were evaluated. Early psychomotor development was normal in patients with D/BMD and BMD. Learning to walk independently after 15 months of age was a risk sign of DMD in nine (36%) patients. Abnormality in crawling was seen in 13 (54%) patients with DMD. These boys demonstrated initial symptoms earlier than those who learned to crawl normally. Mental retardation was established in five (20%) patients with DMD. Deletions in the dystrophin gene were found in 11 families (48%). They were accumulated (9/11, 82%) in the distal region of the gene.
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PMID:Duchenne and Becker muscular dystrophies: an Estonian experience. 1039 46

Linkage analysis was performed on a four-generation family with nonspecific mental retardation (MRX59). The five affected males, ranging in age from 2 years to 52 years, have a normal facial appearance and mild to severe mental impairment. Four obligate carriers are physically normal and not retarded. A maximum LOD score of 2.41 at straight theta = 0.00 was observed with the microsatellite markers, DMD45 in Xp21.2, DXS989 in Xp22.1, and DXS207 in Xp22.2. Recombinations were detected within the dystrophin gene (DMD) in one of the affected males and between DXS207 and DXS987 in Xp22.2 in one of the carriers. These recombinants define the proximal and distal boundaries of a candidate gene region. Genetic localization of this familial condition made prenatal diagnosis informative for one of the obligate carriers.
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PMID:Regional localization of a nonspecific X-linked mental retardation gene (MRX59) to Xp21.2-p22.2. 1039 41

We report a 53-year-old Japanese male with a 47,XXX karyotype. His clinical features included hypoplastic scrotal testes (4 ml bilaterally), normally formed small penis (3.8 cm), relatively poor pubic hair development (Tanner stage 3), gynecomastia, age-appropriate male height (159.1 cm), and mental retardation (verbal IQ of 56). Serum testosterone was markedly reduced (0.6 nmol/L). A needle biopsy showed severe testicular degeneration. FISH analysis revealed complex mosaicism consisting of (1) 47,XXX cells with a single copy of SRY (n = 177), two copies of SRY (n = 3), and no SRY (n = 1); (2) 46,XX cells with a single copy of SRY (n = 9) and no SRY (n = 3); (3) 45,X cells with no SRY (n = 5); and (4) 48,XXXX cells with a single copy of SRY (n = 1) and two copies of SRY (n = 1). PCR analysis showed the presence of Yp portion with the breakpoint between DYS264 and AMELY. Microsatellite analysis demonstrated three alleles for DMD and AR. X-inactivation analysis for the methylation status of the AR gene showed random inactivation of the three X chromosomes. The results suggest that this 47,XXX male has resulted from abnormal X-Y interchange during paternal meiosis and X-X nondisjunction during maternal meiosis. Complex mosaicism may be due to the age-related increase in mitotic nondisjunction which is prone to occur in rapidly dividing lymphocytes and to the presence of two randomly inactivated X chromosomes which may behave asynchronously during mitosis, and clinical features of this male would primarily be explained by the genetic information on the SRY (+) der(X) chromosome and his advanced age.
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PMID:47,XXX male: A clinical and molecular study. 1117 81

Duchenne/Becker muscular dystrophy (DMD/BMD) are the most common inherited muscular diseases caused by mutations in the dystrophin gene. The identification of novel dystrophins in the brain has recently implicated its absence or malfunction etiologically in mental retardation (MR). We therefore examined the relationship between molecular abnormalities and clinical phenotypes. Deletions of the dystrophin gene were analyzed in a total of 137 DMD/BMD patients (DMD 94, BMD 43) to determine central nervous system (CNS) symptoms. The mental capacity was assessed and patients with IQs below 70 were defined as mentally retarded. Thirty-nine percent of DMD boys and 12% of BMD patients were classified as mentally retarded. Eight DMD and 2 BMD patients were diagnosed as having autism. Forty-four percent of DMD and 79% of BMD patients had deletions in the dystrophin gene. All the DMD/BMD patients with deletions upstream of the 5' end of the gene were mentally normal. All of DMD/BMD patients with MR and/or autism had deletions containing the 3' end, although some patients with similar deletions were mentally normal. Our data suggest that Dp140, Dp71 and/or Dp116, the C-terminal translational products of dystrophin, may be related to MR and/or autism in DMD/BMD. However, there was an exception in our series. Three of eight sibling pairs in our cases had different phenotypes, although they had the same mutations in the dystrophin gene. Thus the CNS phenotypes were not determined by the mutations of dystrophin gene alone, and the interaction of dystrophin with other nuclear genes may play important roles.
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PMID:[Central nervous system involvements in Duchenne/Becker muscular dystrophy]. 1172 14

Analyses of deletions in the dystrophin gene and of cognitive status were performed on patients with Duchenne (DMD) or Becker (BMD) muscular dystrophy in order to find a correlation between both features. Molecular study by multiplex and simplex PCR of dystrophin exons led to the identification of 51 deletions in 126 unrelated patients. Most of them were frameshift, in full agreement with severe clinical symptoms, three patients with a BMD-like phenotype had in-frame mutations. Deletions were localized with reference to the different dystrophin isoform sequences and were clustered in two main areas, 5' and central+ 3' end of the gene. Cognitive abilities were tested in 47 out of 51 patients with identified mutations, 23 of them being mentally impaired. Comparison of molecular and neuropsychological features showed that deletions localized in central and 3' parts of the gene (18 out of 23) are preferentially associated with mental impairment. Fourteen of them were found in the regulatory and coding sequences for the three CNS specific carboxy terminal isoforms. Therefore, though mutations with variable locations may lead to cognitive impairment, our results show that deletions in the distal portion of the gene are basically related to mental retardation.
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PMID:Dystrophin deletions and cognitive impairment in Duchenne/Becker muscular dystrophy. 1497 63

IL1RAPL1 (interleukin-1 receptor accessory protein-like, gene 1) has recently been shown to be mutated in patients with X-linked mental retardation. Clinical experience has suggested that patients with the contiguous gene syndrome, complex glycerol kinase deficiency (cGKD), will have mental retardation (MR) if they have deletions extending from the GK gene into the DMD gene and/or involving a significant extension telomeric from DAX1. We examined cell lines from patients with cGKD whose clinical features would be informative and would allow us to determine if IL1RAPL1 deletions can help to explain the MR in patients with deletions extending telomeric from DAX1. Our results showed that nearly all patients with deletions involving DAX1, but not DMD, had MR if IL1RAPL1 was deleted. If ILIRAPLI and DMD were intact, the patients with DAX1 deletions only rarely had normal development. Deletions in DNA from patients with cGKD who exhibited MR and had normal IL1RAPL1 all involved the GK and DMD genes. Our data are consistent with the association of IL1RAPL1 gene deletion and MR in the majority of patients with cGKD and deletions extending telomeric from DAX1.
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PMID:IL1RAPL1 is associated with mental retardation in patients with complex glycerol kinase deficiency who have deletions extending telomeric of DAX1. 1530 Aug 57

Common fragile sites (CFSs) are large regions of profound genomic instability found in all individuals. They are biologically significant due to their role in a number of genomic alterations that are frequently found in many different types of cancer. The first CFS to be cloned and characterized was FRA3B, the most active CFS in the human genome. Instability within this region extends for over 4.0 Mbs and contained within the center of this CFS is the FHIT gene spanning 1.5 Mbs of genomic sequence. There are frequent deletions and other alterations within this gene in multiple tumor types and the protein encoded by this gene has been demonstrated to function as a tumor suppressor in vitro and in vivo. In spite of this, FHIT is not a traditional mutational target in cancer and many tumors have large intronic deletions without any exonic alterations. There are several other very large genes found within CFS regions including Parkin (1.37 Mbs in FRA6E), GRID2 (1.47 Mbs within 4q22.3), and WWOX (1.11 Mbs within FRA16D). These genes also appear to function as tumor suppressors but are not traditional mutational targets in cancer. Each of these genes is highly conserved and the regions spanning them are CFSs in mice. We have now examined lists of the largest human genes and found forty that span over one megabase. Many of these are derived from chromosomal bands containing CFSs. BACs within these genes are being utilized as FISH probes to determine if these are also CFS genes. Thus far we have identified the following as CFS genes: CNTNAP2 (2.3 Mbs in FRA7I), DMD (2.09 Mbs in FRAXC), LRP1B (1.9 Mbs in FRA2F), CTNNA3 (1.78 Mbs in FRA10D), DAB1 (1.55 Mbs in FRA1B), and IL1RAPL1 (1.36 Mbs in FRAXC). Although, these genes are also not traditional mutational targets in cancer they do exhibit loss of expression in multiple tumor types suggesting that they may also function as tumor suppressors. Many of the large CFS genes are involved in neurological development. Parkin is mutated in autosomal recessive juvenile Parkinsonism and deletions in mice are associated with the mouse mutant Quaking (viable). Spontaneous mouse mutants in GRID2 and DAB1 are associated with Lurcher and Reelin, respectively. In humans, alterations in IL1RAPL1 cause X-linked mental retardation and loss of WWOX is associated with Tau phosphorylation. We propose that the instability-induced alterations in these genes contribute to cancer development in a two-step process. Initial alterations will primarily occur within intronic regions, as these genes are greater than 99% intronic. These are not benign. Instead, they alter the repertoire of transcripts produced from these genes. As cancer progresses deletions will begin to encompass exons resulting in gene inactivation. These two types of alterations occurring in multiple large CFS genes may contribute significantly to the heterogeneity observed in cancer. There are also important potential linkages between normal neurological development and the development of cancer mediated by alterations in these genes.
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PMID:Common fragile sites, extremely large genes, neural development and cancer. 1622 25

Genomic copy-number variations (CNVs) involving large DNA segments are known to cause many genetic disorders. Depending on the changes, they are predicted to lead either to decreased or an increased gene expression. However, the ability to detect smaller exonic copy-number changes has not been explored. Here we describe a new oligonucleotide-based comparative genomic hybridization (CGH)-array approach for high-throughput detection of exonic deletions or duplications and its application to deletion/duplication analyses of the genes encoding CFTR, six sarcoglycans (SGCA, SGCB, SGCG, SGCD, SGCE, and SGCZ), and DMD. In this work we show the successful development of an array format containing 158 exons that collectively span eight genes and its clinical application for the rapid screening of deletions and duplications in a diagnostic setting. We have analyzed a series of 35 DNA samples from patients affected with cystic fibrosis (CF), Duchenne and Becker muscular dystrophies (DMD/BMD), or sarcoglycanopathies, and have characterized exonic copy-number changes that have been validated with other methods. Interestingly, even heterozygous deletions and duplications of only one exon, as well as mosaic deletions, were detected by this CGH approach. Our results showed that the resolution is very high, as abnormalities of about 1.5-2 kb could be detected. Since this approach is completely scalable, this new molecular tool will allow the screening of combinations of genes involved in a particular group of clinically and genetically heterogeneous disorders such as mental retardation, muscular dystrophies and brain malformations.
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PMID:Detection of exonic copy-number changes using a highly efficient oligonucleotide-based comparative genomic hybridization-array method. 1875 6

A child with global developmental delay sparing motor skills evolving into later intellectual disability with a consistently normal neuromuscular examination was discovered to have a dystrophin specific mutation in the 3' end of the gene. The deletion in the DMD gene was unsuspected and discovered through array comparative genomic hybridization and confirmed on polymerase chain reaction analysis. This case shows a central nervous system-specific and restrictive phenotype for a disorder that is conceptualized as being progressively neuromuscular in clinical expression. Given the familial and therapeutic implications for accurate diagnosis of DMD mutations, this case raises the possible need for screening boys with global developmental delay/intellectual disability even in the absence of any overt muscle weakness and further shows the utility of comparative genomic hybridization (CGH) analysis in the evaluation of patients with nonsyndromic mental retardation.
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PMID:An instructive case of an 8-year-old boy with intellectual disability. 1907 14


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