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)

Cognitive impairment occurs in one-third of patients with Duchenne muscular dystrophy, a lethal X-linked, recessive disease caused by mutations in the dystrophin gene which is expressed in both brain and muscle, the two transcripts having alternative first exons. Previous reports have indicated that the 'brain-type' dystrophin transcript predominates in brain. Using in situ hybridisation with antisense oligonucleotides, expression of four distinct mRNAs in specific brain areas is demonstrated here; the 14 kb muscle-type and brain-type transcripts were found to coexist in cortical and hippocampal neurons and two new transcripts have been identified in dentate gyrus and cerebellar Purkinje neurons, respectively. The latter has a novel first exon which was isolated and sequenced from mouse and human, and which would encode a protein with a different amino-terminus from the known muscle- and brain-type isoforms. Mapping in human located this exon in a large intron between the muscle-type promoter and second exon of the dystrophin gene. This finding of four alternative transcripts regulated by different promoters in brain reveals a new complexity to dystrophin expression that may have important insights for mental retardation mechanisms.
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PMID:Expression of four alternative dystrophin transcripts in brain regions regulated by different promoters. 130 51

Dystrophin, the protein product defective in Duchenne muscular dystrophy (DMD), is present in all types of muscle and in the brain. The function of the protein is unknown and its role in the brain is unclear, although 30% of DMD patients show nonprogressive mental retardation. We have therefore studied the localisation of dystrophin in cultures of normal and DMD human fetal neurons using antibodies raised to different regions of the protein. Dystrophin immunoreactivity was demonstrated in the soma and axon hillock of normal neurons and appeared to be associated with the inner part of the cell membrane, although some intracellular staining was also observed. Positive dystrophin staining was present only in cells with fully developed neuronal features, although not all the neurons were positive. Glial cells were always negative for the antigen. Immunostaining with antibodies to the brain spectrins indicate that the dystrophin antibodies did not crossreact with these proteins. The possibility of cross-reactivity with other proteins is discussed. Studies of cells cultured from a DMD fetus also showed specific dystrophin immunostaining in neurons, although the muscle was generally negative for dystrophin. However, the localisation of dystrophin immunostaining and that of the brain spectrins and neurofilaments appeared abnormal, as did the overall morphology of the cells. This suggests that dystrophin may play a role during brain development and dystrophin deficiency results in abnormal neuronal features. This would be consistent with the nonprogressive nature of the mental retardation observed in DMD patients.
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PMID:Dystrophin immunoreactivity in normal and Duchenne human fetal neurons in culture. 137 3

We studied the central nervous system (CNS) of control mice in comparison with that of mdx mice, immunohistochemically and immunoelectrophoretically, using 5 kinds of polyclonal antibodies against dystrophin (DMDP-II, 60-kDa, 30-kDa, P-20 and DMDP-IV) to determine whether or not and, if so, how dystrophin exists in the central nervous system. A positive dystrophin reaction was seen on the neurons and glial cells in both control and mdx tissue, without any immunohistochemical difference. In control mice, Western blot analysis showed two relatively clear bands corresponding to 400-kDa, with all 4 antibodies used (60-kDa, 30-kDa, P-20 and DMDP-IV), and 280-kDa, with 3 of them, the exception being 30-kDa, and 2 other faint bands corresponding to larger M(r) than 400-kDa, with 3 of them, the exception being P-20, respectively. In the mdx CNS, the 400-kDa band was absent, the other 3 bands being seen. The results suggest that dystrophin really exists in the control CNS, and some dystrophin isoforms or cross-reactive proteins exist on the neurons and glial cells in mdx as well as control mice. The localization of dystrophin in CNS also suggests its physiological function in the conduction system rather than a mechanical one, and a defect of it in CNS is a possible cause of the mental retardation in Duchenne muscular dystrophy.
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PMID:Dystrophin isoforms and/or cross-reactive proteins on neurons and glial cells in control and mdx central nervous systems. 151 55

Gene localization was determined by linkage analysis in 5 families with non-specific X-linked mental retardation (MRX) and were MRX1, Xp11.4-q21.31; MRX10, Xp21.3-p11.4; MRX11, Xp21.3-p11.22; MRX12, Xp21.3-q21.1; and MRX13, Xp22.3-q21.22. Four of these localizations cross the dystrophin brain promoter, a candidate locus for MRX. None of the affected individuals who were tested showed variation suggestive of a deletion. No consistent clinical features were observed between or within 4 of the 5 families. In MRX12, prematurity or low birth weight, hypotelorism and short stature were seen in several affected males. Heterozygote manifestations occurred in 3 families. There was no evidence to suggest involvement of the same gene in more than one family, nor to clinically separate these families into distinct genetic entities. Non-overlapping localizations for MRX1 and MRX10 demonstrate the existence of at least 2 separate loci among these 5 families.
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PMID:Localization of non-specific X-linked mental retardation genes. 160 17

Thirty per cent of boys with Duchenne muscular dystrophy (DMD) suffer from various degrees of mental retardation. Since dystrophin, the protein absent in muscles of boys with DMD, is produced also in the brain, it was postulated that the deficiency of brain dystrophin might account for the mental retardation found in DMD boys. The mdx mouse, a mouse model of DMD, fails to produce dystrophin in muscle and brain. This prompted us to study the cognitive function of these animals. Learning and memory processes were studied in 10 mdx females and 9 genetically matched controls using the passive avoidance test. Statistically significant differences in the retention of the passive avoidance response was detected between mdx and control mice, indicating an impairment in passive avoidance learning in mdx mice. Our data reinforce the view that brain dystrophin deficiency is correlated with cognitive dysfunction and indicate that mdx mice might be a model for the mental retardation found in DMD boys.
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PMID:Passive avoidance behaviour deficit in the mdx mouse. 182 82

A total of 162 Duchenne (DMD) patients and two girls with a DMD phenotype were analysed for deletions in the central region of the dystrophin gene in order to determine if there was a correlation between mental retardation (MR) and the pattern of deletion. Approximately 43% of the patients studied had deletions with two dystrophin cDNAs, cf23a and cf56a, and among 148 patients who were mentally assessed, 50% were mentally retarded. The average IQ in the group of patients with DNA deletions did not differ significantly from those patients with no detectable deletions. However, six unrelated DMD boys with MR showed an identical pattern of deletion. Our observations in the group of patients who had detected DNA deletions suggest that exon 52 of the dystrophin gene may be functionally significant in the manifestation of MR: 70% (19/27) of patients with a deletion of this exon were mentally retarded, whereas only 38% (15/39) of MR patients had deletions not involving exon 52. This difference was statistically significant.
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PMID:Apparent association of mental retardation and specific patterns of deletions screened with probes cf56a and cf23a in Duchenne muscular dystrophy. 187 22

Dystrophin, the protein product of the Duchenne muscular dystrophy gene, is expressed in brain as well as muscle. The role of dystrophin in the brain is not clear, though one-third of Duchenne muscular dystrophy patients exhibit some degree of mental retardation. We have isolated the genomic region encoding the alternative 5' terminus of dystrophin used in the brain. Primer extension and polymerase chain reaction assays on RNA demonstrate that this region contains an alternative promoter for dystrophin used in the brain. Physical mapping of this region indicates that this brain promoter is located greater than 90 kilobases 5' to the promoter used in muscle and 400 kilobases from exon 2 to which it is spliced. The large physical distance between the promoters, taken together with their known tissue selectivities, suggests that in certain patients a deletion of either dystrophin promoter might give rise to reduced dystrophin expression selective to brain or muscle. We have identified one such individual with specific deletion of the dystrophin muscle promoter, giving rise to Becker muscular dystrophy, and we predict that specific loss of the brain promoter may be one cause of X chromosome-linked mental retardation.
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PMID:Dystrophin is transcribed in brain from a distant upstream promoter. 199 28

X-linked DMD is a serious condition characterized by progressive muscle wasting and weakness and death ensues in the late teens or early twenties. There is considerable clinical variability even within families and some suggestions of genetic heterogeneity. Though skeletal muscle is primarily involved, other tissues are also affected including cardiac and smooth muscle. Other abnormalities include mental retardation, thymus hyperplasia and possibly certain endocrinological changes. The responsible locus is at Xp21 and the gene product is a very large protein (dystrophin) which is normally localised to muscle cell membranes. It is hypothesised that its absence in DMD may result in instability of the muscle cell membrane with resultant ingress of calcium, an increase in intracellular calcium, and cell death. An understanding of this pathway is important in devising an effective treatment.
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PMID:Clinical and molecular studies in Duchenne muscular dystrophy. 266 10

Molecular genetics has transformed clinical concepts of Duchenne muscular dystrophy (DMD) in several different ways. (1) The disease can now be defined as a myopathy due to mutation at Xp21, a specific locus on the short arm of the X chromosome. (2) As a consequence of that discovery, any myopathy due to mutation at Xp21 should be a variant of DMD and should affect the same gene product. Moreover, any myopathy due to mutation at a location other than Xp21 should affect some other gene product. (3) For these reasons, DNA analysis is now needed for clinical diagnosis of muscle disease. (4) Xp21 myopathies may be mild or severe, may occur in females even though X-linked, and may be manifest only by high serum levels of creatine kinase. (5) Mental retardation is not consistently related to diseases that are encoded at Xp21. The association of mental retardation with DMD may be due to mutation in a separate gene near that for DMD. Concepts may soon be altered again as we learn about the affected gene product (dystrophin) and its role in these diseases.
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PMID:Clinical concepts of Duchenne muscular dystrophy. The impact of molecular genetics. 328 82

Muscle biopsies from three patients with cardiomyopathy, mental retardation and increased serum creatine kinase levels revealed scattered fibers with tiny intracytoplasmic vacuoles containing basophilic and acid phosphatase-positive material and slightly increased amounts of PAS-positive granules. These findings are consistent with those seen in the so-called lysosomal glycogen storage disease with normal acid maltase. In addition to the vacuoles, there were occasional folds or indentations in the sarcolemma which were connected to the membrane enclosing the vacuoles. These membranes were well demonstrated histochemically by the nonspecific esterase and acetylcholinesterase stains. On electron microscopy, most of the vacuoles were bounded by membranes with basal lamina. The vacuolar membrane stained positively with antibodies raised to dystrophin, dystrophin-associated glycoproteins, laminin and type 4 collagen, and it was identical to the sarcolemma and its basal lamina. Therefore, the membrane abnormality which causes sarcolemmal folding is probably critical to understanding the pathomechanism of this disease.
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PMID:Sarcolemmal indentation in cardiomyopathy with mental retardation and vacuolar myopathy. 753 16


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