Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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

Duchenne and Becker muscular dystrophies are X-linked allelic disorders in which the association of central nervous system dysfunction, typically in the form of mental retardation, is a well recognized feature. They are both due to mutations in the dystrophin gene, whose corresponding protein products are expressed both in the muscle and central nervous system. We have observed an increased frequency of epilepsy in children with Duchenne and Becker muscular dystrophy attending our clinic. Out of 254 boys with this condition (201 Duchenne and 53 Becker), eight children, four in the Duchenne and four in the Becker group, had a confirmed diagnosis of epilepsy (cumulative incidence 3.14%, with a subgroup incidence of 1.99% in the Duchenne and 7.54% in the Becker group). Statistical analysis indicated that only the incidence of epilepsy in Becker muscular dystrophy was significant (p < 0.007). Our data suggests that epilepsy may be a rare associated feature in children with muscular dystrophy secondary to dystrophin deficiency.
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PMID:Epilepsy in Duchenne and Becker muscular dystrophies. 1072 5

Mental retardation is a clinical feature present in both Duchenne and Becker muscular dystrophy patients and its pathogenesis is still unknown. Dp140 is a dystrophin isoform with predominant expression during foetal brain development. Its promoter and first exon lie in the large intron between exon 44 and 45, a region that is commonly deleted in dystrophinopathic patients. We performed neuropsychological evaluation and genetic analysis of the Dp140 transcription unit on 12 Duchenne muscular dystrophy and 28 Becker muscular dystrophy patients carrying deletions in this critical region. Comparison of neuropsychological and molecular data showed that there is a statistically significant relationship between the loss of Dp140 transcription unit and mental retardation in Becker muscular dystrophy patients (P = 0.008). Such a correlation is not evident in Duchenne muscular dystrophy patients but only shows a trend towards significance (P = 0.063). It is worth noting that both Duchenne muscular dystrophy and Becker muscular dystrophy patients with normal intelligence do not show deletions in the Dp140 regulatory regions. In the light of these findings, we suggest that impairment of cognitive abilities in Duchenne muscular dystrophy and Becker muscular dystrophy patients might be related to a dysfunction of Dp140 brain isoform.
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PMID:Loss of Dp140 regulatory sequences is associated with cognitive impairment in dystrophinopathies. 1073 67

Duchenne muscular dystrophy (DMD) and the allelic disorder Becker muscular dystrophy (BMD) are common X-linked recessive neuromuscular disorders that are associated with a spectrum of genetically based developmental cognitive and behavioral disabilities. Seven promoters scattered throughout the huge DMD/BMD gene locus normally code for distinct isoforms of the gene product, dystrophin, that exhibit nervous system developmental, regional and cell-type specificity. Dystrophin is a complex plasmalemmal-cytoskeletal linker protein that possesses multiple functional domains, autosomal and X-linked homologs and associated binding proteins that form multiunit signaling complexes whose composition is unique to each cellular and developmental context. Through additional interactions with a variety of proteins of the extracellular matrix, plasma membrane, cytoskeleton and distinct intracellular compartments, brain dystrophin acquires the capability to participate in the modulatory actions of a large number of cellular signaling pathways. During neural development, dystrophin is expressed within the neural tube and selected areas of the embryonic and postnatal neuraxis, and may regulate distinct aspects of neurogenesis, neuronal migration and cellular differentiation. By contrast, in the mature brain, dystrophin is preferentially expressed by specific regional neuronal subpopulations within proximal somadendritic microdomains associated with synaptic terminal membranes. Increasing experimental evidence suggests that in adult life, dystrophin normally modulates synaptic terminal integrity, distinct forms of synaptic plasticity and regional cellular signal integration. At a systems level, dystrophin may regulate essential components of an integrated sensorimotor attentional network. Dystrophin deficiency in DMD/BMD patients and in the mdx mouse model appears to impair intracellular calcium homeostasis and to disrupt multiple protein-protein interactions that normally promote information transfer and signal integration from the extracellular environment to the nucleus within regulated microdomains. In DMD/BMD, the individual profiles of cognitive and behavioral deficits, mental retardation and other phenotypic variations appear to depend on complex profiles of transcriptional regulation associated with individual dystrophin mutations that result in the corresponding presence or absence of individual brain dystrophin isoforms that normally exhibit developmental, regional and cell-type-specific expression and functional regulation. This composite experimental model will allow fine-level mapping of cognitive-neurogenetic associations that encompass the interrelationships between molecular, cellular and systems levels of signal integration, and will further our understanding of complex gene-environmental interactions and the pathogenetic basis of developmental disorders associated with mental retardation.
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PMID:Brain dystrophin, neurogenetics and mental retardation. 1075 78

X-linked mental retardation is estimated to affect approximately 1 in 600 males. Although numerous genes responsible for syndromic mental retardation have been identified, the study of non-syndromic mental retardation suffers from intrinsic issues of genetic heterogeneity. During the investigation of three brothers with a contiguous gene deletion syndrome of Becker muscular dystrophy, glycerol kinase deficiency, congenital adrenal hypoplasia, and mental retardation, we found their dystrophin gene to be fused tail-to-tail with a gene encoding a novel member of the interleukin-1 receptor family, IL1RAPL1. This gene has a close relative in Xq22, which we call IL1RAPL2. Both IL1RAPL1 and IL1RAPL2 have novel C-terminal sequences not present in other related proteins, and are encoded by very large genes. The 1.8-megabase deletion in these patients removes not only the last exon of the dystrophin gene, the entire glycerol kinase and DAX-1 genes, and the MAGE-B gene cluster, but also three exons encoding the intracellular signalling domain of IL1RAPL1. The literature contains multiple reports of patients with non-syndromic mental retardation in association with an Xp22.1-Xp21.3 microdeletion of a marker which lies within the IL1RAPL1 gene. The gene is also wholly or partially deleted in patients with mental retardation as part of a contiguous deletion syndrome. We suggest that IL1RAPL1, and perhaps IL1RAPL2, are strong candidates for X-linked non-syndromic mental retardation loci, and that molecules resembling IL-1 and IL-18 play a role in the development or function of the central nervous system.
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PMID:Two novel members of the interleukin-1 receptor gene family, one deleted in Xp22.1-Xp21.3 mental retardation. 1075 39

Osteoporosis screening of adults ages 40 to 60 who attended community-based adult training centers was conducted utilizing dual-energy X-ray absorptiometry (DEXA) measurements of the calcaneus. Valid measurements were obtained on 107 individuals, a response rate of 94%. One fifth of the sample (21%) had osteoporosis and 34% had osteopenia. On multiple regression analysis, the most significant predictors of BMD were Down syndrome, mobility status, and race. Future studies involving larger samples of middle-age adults with mental retardation/developmental disabilities will clarify the need and optimum age for osteoporosis screening.
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PMID:Screening for osteoporosis in community-dwelling adults with mental retardation. 1098 Nov 93

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

DNA copy number variation is an important cause of genetic disease. There are several techniques available to detect copy number changes of various sizes, each with their limitations in resolution and cost. Here we outline the development of multiplex amplifiable probe hybridization (MAPH) into a high-throughput diagnostic technique for detecting copy number variation of almost any size. Its application in testing for genetic mutations causing diseases, such as familial breast cancer, Charcot-Marie-Tooth disease Type 1A, Duchenne/Becker muscular dystrophy and familial colorectal cancer is described, as well as its use in identifying chromosomal changes in some individuals with mental retardation. The analysis of the data produced by MAPH is also considered, along with its potential for automation and development of microarray-based MAPH.
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PMID:DNA copy number analysis by MAPH: molecular diagnostic applications. 1213 2

We report the characterization of two deep intronic mutations in the Duchenne muscular dystrophy (DMD) gene of two unrelated Becker muscular dystrophy (BMD) patients, causing the aberrant inclusion of a pseudoexon in the mature transcripts. These two mutations were identified by the use of RT-PCR on transcripts isolated from muscle. The first abnormally large transcript resulting from a 58-bp insertion between exon 62 and exon 63 was identified in a BMD patient with mental retardation. The origin of this transcript was a mutation in intron 62 (IVS62-285A>G), which resulted in the occurrence of a high quality donor splice site. The IVS25+2036A>G in intron 25 was identified in a subclinical BMD patient with high CK levels. The mutation reinforces the strength of a pre-existing acceptor splice site, resulting in activation of an intronic pseudoexon of 95 bp. By using DHPLC, the patient's mother was found to be a somatic mosaic. The insertion of these newly recognized extra exons leads to premature termination codons, but we could observe that some degree of normal splicing was taking place in both patients. The detection of these residual full length transcripts is consistent with the clinical presentation and dystrophin analyses. This is the first report of pseudoexon activation as a mechanism for Becker muscular dystrophy, and this reveals further the diversity of genetic abnormalities causing BMD.
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PMID:Pseudoexon activation in the DMD gene as a novel mechanism for Becker muscular dystrophy. 1275 7


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