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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expansion of trinucleotide repeats is now recognized as a major cause of neurological disease. At least seven disorders result from trinucleotide repeat expansion: X-linked spinal and bulbar muscular atrophy (SBMA), two fragile X syndromes of mental retardation (FRAXA and FRAXE), myotonic dystrophy, Huntington's disease, spinocerebellar ataxia type 1 (SCA1), and dentatorubral-pallidoluysian atrophy (DRPLA). The expanded trinucleotide repeats are unstable, and the phenomenon of anticipation, i.e., worsening of disease phenotype over successive generations, correlates with increasing expansion size. In this review, we compare the clinical and molecular features of the trinucleotide repeat diseases, which may be classified into two types. Fragile X and myotonic dystrophy are multisystem disorders usually associated with large expansions of untranslated repeats, while the four neurodegenerative disorders, SBMA, Huntington's disease, SCA1, and DRPLA, are caused by smaller expansions of CAG repeats within the protein coding portion of the gene. CAG repeats encode polyglutamine tracts. Polyglutamine tract expansion thus appears to be a common mechanism of inherited neurodegenerative disease. Although polyglutamine tract lengthening presumably has a toxic gain of function effect in the CAG trinucleotide repeat disorders, the basis of this neuronal toxicity remains unknown.
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PMID:Trinucleotide repeat expansion in neurological disease. 799 66

The triplet repeat sequences (CGG)n, (GCT)n, and (CAG)n, which naturally occur in the human genome, can be autonomously expanded in human DNA by an as yet unknown mechanism. These in part excessive expansions have been causally related to human genetic diseases, the fragile X (Martin-Bell) syndrome, to myotonic dystrophy (Curschmann-Steinert), to spinal and bulbar muscular atrophy (Kennedy disease), and recently to Huntington disease. A GCC trinucleotide repeat was found to be expanded and methylated in the fragile site FRAXE on the human X chromosome. These findings were associated with mental retardation (Knight et al., 1993). In spinocerebellar ataxia type 1 (SCA1), a polymorphic CAG repeat was found to be unstable and expanded in individuals with that disease (Orr et al., 1993). We have demonstrated in in vitro experiments that the synthetic oligodeoxyribonucleotides (CGG)17, (CGG)12, (GCC)17, (CG)25, (CTG)17, or (CAG)17 plus (GTC)17, in the absence of added natural DNA, can be expanded with Taq polymerase in the polymerase chain reaction (PCR). Some expansion can already be detected after 4 PCR cycles. The E. coli Klenow DNA polymerase also functions in a similar amplification and expansion reaction performed at 37 degrees C without cycling. Other oligodeoxyribonucleotides, like, (CGG)7, (CGGT)13, or (TAA)17, are devoid of this property or have very low activity. The cytidine-methylated polymers (GCC)17 or (CG)25 yield expansion products of considerably reduced chain lengths. The expansion of the polymer (CGG)17 is affected by cytidine methylation to a lesser degree. A specific sequence and/or secondary structure and high CG content appear to be requirements for this expansion reaction by a possible slippage mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enzymatic amplification of synthetic oligodeoxyribonucleotides: implications for triplet repeat expansions in the human genome. 811 62

The recent observation that the mutation underlying a number of genetic diseases including fragile sites, FRAXA and FRAXE (associated with mental retardation), myotonic dystrophy, spinal and bulbar muscular atrophy (Kennedy's disease), Huntington's disease and spinocerebellar ataxia type 1 are caused by the expansion of a trinucleotide repeat sequence will lead to interest in the identification of such sequences in regions related to other diseases. We report here the identification of all ten classes of trinucleotide repeats within a 2 Mbp region of 4p16.3 containing the Huntington's disease (HD) gene. Fifty one triplet repeats were identified and localised on a high resolution restriction map of a cosmid contig covering this region. This included the triplet repeat (CAG)n, which has subsequently been shown to be expanded in Huntington's disease patients.
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PMID:Distribution of trinucleotide repeat sequences across a 2 Mbp region containing the Huntington's disease gene. 816 55

Trinucleotide repeat expansion is increasingly recognized as a cause of neurogenetic diseases. To date, seven diseases have been identified as expanded repeat disorders: the fragile X syndrome of mental retardation both FRAXA and FRAXE loci), myotonic dystrophy, X-linked spinal and bulbar muscular atrophy, Huntington's disease, spinocerebellar ataxia type I, dentatorubral-pallidoluysian atrophy, and Machado-Joseph disease. All are neurologic disorders, affecting one or more regions of the neuraxis. Moreover, five of the seven (the last five above) are progressive neurodegenerative disorders whose strikingly similar mutations suggest a common mechanism of neuronal degeneration. In this article we discuss specific characteristics of each trinucleotide repeat disease, review their shared clinical and genetic features, and address possible molecular mechanisms underlying the neuropathology in each disease. Particular attention is paid to the neurodegenerative diseases, all of which are caused by CAG repeats encoding polyglutamine tracts in the disease gene protein.
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PMID:Trinucleotide repeats in neurogenetic disorders. 883 37

The human genome has many nucleotide repeat sequences. These range from a single repeating base to entire duplicated genes. Expansion of repeating triplets of nucleotides in the genome has recently been associated with nine degenerative and developmental neuropsychiatric diseases: fragile X syndrome, fragile X-linked mental retardation, myotonic dystrophy, Friedreich's ataxia, spinal and bulbar muscular atrophy, Huntington's disease, spinocerebellar ataxia type 1, dentatorubral-pallidoluysian atrophy, and Machado-Joseph disease. These diseases are all conditions of the central nervous system; in all of them, the inheritance pattern usually exhibits the phenomenon of anticipation (defined as progressively earlier age of onset or a worsening disease severity over successive generations), and the severity of the phenotypic expression and penetrance appears to be related to the extent of the triplet expansion. Identification of this pathological genetic phenomenon solves several of the mysteries that surrounded these conditions but raises many important questions regarding pathogenic mechanisms that may be shared. There is some indication that triplet expansions may also underlie other neuropsychiatric conditions such as schizophrenia or bipolar disorder.
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PMID:Triplet repeat gene sequences in neuropsychiatric diseases. 938 23

The rat androgen-binding protein/sex hormone-binding globulin (ABP/SHBG) gene is regulated by promoters P1 and PA. P1 regulates the mRNA encoding secreted ABP/SHBG, whereas PA regulates an alternate mRNA which encodes a modified protein that is targeted to the nucleus. Promoter PA is GC rich, consisting of 70-80% GC residues. During routine BLAST sequence analysis it was discovered that this GC-rich region is highly related to the human fragile X-related protein 2 (FXR-2) 5'-untranslated RNA sequence. Furthermore, the nucleotide coding sequence of the initial 14 FXR-2 amino acid residues was identical in the ABP/SHBG gene. The 5'-untranslated FXR-2 sequence contains triplet (CGG) repeats, which are also present in the rat ABP/SHBG gene. The meiotic instability of CGG repeats in the human fragile X (FMR1) gene causes the fragile X mental retardation syndrome. The data presented here suggest that the ABP/SHBG and FXR-2 genes overlap with each gene transcribed in the opposite direction. In support of this structure, the human ABP/SHBG and the FXR-2 genes map to the same site on chromosome 17. Thus, the ABP/SHBG gene contains triplet repeats in the alternate promoter PA. It will be of particular interest to determine if triplet instability affects ABP/SHBG gene expression. A triplet instability in the X-linked androgen receptor gene causes spinal and bulbar muscular atrophy.
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PMID:The rat androgen-binding protein (ABP/SHBG) gene contains triplet repeats similar to unstable triplets: evidence that the ABP/SHBG and the fragile X-related 2 genes overlap. 943 88

We report on three brothers with mental retardation and a contracted CAG repeat in the androgen receptor (AR) gene. It is known that expansion of the CAG repeat in this gene leads to spinal and bulbar muscular atrophy (SBMA or Kennedy disease); however, contracted repeats have not yet been implicated in disease. As the range of the length of CAG repeats in the AR gene, like those of other genes associated with dynamic mutations, follows a normal distribution, the theoretical possibility of disease at both ends of the distribution should be considered.
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PMID:CAG repeat contraction in the androgen receptor gene in three brothers with mental retardation. 1039 29

X-linked alpha-thalassemia/mental retardation syndrome (ATR-X) is a syndromic form of X-linked mental retardation. We investigated the X-inactivation status of nine female ATR-X carriers by methylation-specific PCR of the HUMARA gene. Six carriers demonstrated a skewed X-inactivation pattern (>90:10) and one showed a non-skewed pattern (72:28), while two were uninformative because of homozygosity for the CAG repeat polymorphic alleles in the HUMARA. Only the carrier mother who showed non-skewed X-inactivation had moderate mental retardation. These findings suggest that mutations in ATRX may cause mental retardation in females, if the X chromosome carrying mutated ATRX is not properly inactivated.
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PMID:Non-skewed X-inactivation may cause mental retardation in a female carrier of X-linked alpha-thalassemia/mental retardation syndrome (ATR-X): X-inactivation study of nine female carriers of ATR-X. 1610 Jul 24

Humans show considerable additive genetic variance in cognitive ability or general intelligence (g) but the genes that influence this variation are largely unknown. It is suggested here that the X-linked androgen receptor gene (AR) has a major modifying effect on speed of neuronal transmission and thus on g. The AR is polymorphic in its N-terminal transactivation domain which encodes a polyglutamine tract (CAGn) with a parametric mean of n=21 CAG repeats and normal variation between n=11 and n=30 repeats . Very low repeat numbers are associated with mental retardation, repeat numbers above 30 with reduced cognitive function, and CAGn greater than 40 with spinal and bulbar muscular atrophy. Within the range of 11-30 repeats short CAG chains are associated with high androgen sensitivity and high sperm counts. Despite this, all human populations contain many individuals with n>21 repeats. I suggest that within the range of 11-30 repeats there is a positive association with speed of neuronal transmission and values of g. The advantage of high g and the consequent spread of alleles for high CAGn will be countered by the negative effects on sperm production. Below CAGn=11 and above CAGn=30 neuronal speed may reduce, thus leading to reductions in g and loss of function of neurons. In support of the model I discuss the link between the X-chromosome and g, the comparative structure of the AR gene in the primates, and the variation in CAGn and g in human ethnic groups.
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PMID:The androgen receptor gene: a major modifier of speed of neuronal transmission and intelligence? 1705 85

The term "junk DNA" has been reconsidered following the delineation of the functional significance of repetitive DNA regions. Typically associated with centromeres and telomeres, DNA repeats are found in nearly all organisms throughout their genomes. Repetitive regions are frequently heterochromatinized resulting in silencing of intrinsic and nearby genes. However, this is not a uniform rule, with several genes known to require such an environment to permit transcription. Repetitive regions frequently exist as dinucleotide, trinucleotide, and tetranucleotide repeats. The association between repetitive regions and disease was emphasized following the discovery of abnormal trinucleotide repeats underlying spinal and bulbar muscular atrophy (Kennedy's disease) and fragile X syndrome of mental retardation (FRAXA) in 1991. In this review, we provide a brief overview of epigenetic mechanisms and then focus on several diseases caused by DNA triplet-repeat expansions, which exhibit diverse epigenetic effects. It is clear that the emerging field of epigenetics is already generating novel potential therapeutic avenues for this group of largely incurable diseases.
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PMID:Epigenetics and Triplet-Repeat Neurological Diseases. 2673 36


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