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)

Chromosome imbalance (aneusomy) is the leading known cause of both spontaneous abortion and mental retardation in human beings. The primary abnormality is thought to result from quantitative changes of transcription products from the unbalanced genetic material. To document this point, I compared chromosome 21-specific transcription in skin fibroblasts from subjects with monosomy 21, disomy 21 (normal), and trisomy 21 (Down syndrome). Polyadenylylated RNA [poly(A)-RNA], which is enriched in messenger and messenger-precursor RNA sequences, was isolated from the above fibroblast lines. Radioactive DNA (cDNA) complementary to these RNAs was synthesized with reverse transcriptase (RNA-dependent DNA polymerase). These cDNAs were hybridized with (i) DNA from a cell line with a mouse genome plus human chromosome 21 and (ii) mouse DNA. Subtraction of the amount of hybridization in experiment ii from that in experiment i yielded a measure of human chromosome 21-specific RNA sequences. The results were consistent with gene dosage at the transcriptional level; for monosomy 21-derived cDNA, 0.6% (of the total cDNA) hybridized specifically to human chromosome 21; for disomy 21-derived cDNA, 2% hybridized; and for trisomy 21-derived cDNA, 3% hybridized. Thus, for DNA sequences on chromosome 21 in human skin fibroblasts, transcription depends on DNA dosage. Characterization of the chromosome 21-specific RNA sequences quantitated in these experiments could help to elucidate the mechanisms by which abnormal karyotypes result in abnormal phenotypes.
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PMID:Down syndrome: gene dosage at the transcriptional level in skin fibroblasts. 15 66

The genetic basis of retinoblastoma is reviewed and the following conclusions are drawn: 1) The mode of inheritance of the hereditary variety of retinoblastoma (R) is autosomal dominant with about 90% penetrance. 2) About 68% of inherited cases are bilateral, and about 32%, unilateral. There is an intrafamilial correlation between penetrance as measured by segregation ratio and expressivity as measured by the fraction of bilaterally affected patients. 3) The vast majority of all R patients are sporadic cases, i.e., they are the only affected members of otherwise unaffected families. The porportion of bilateral cases is much lower among sporadic than among hereditary cases. 4) All bilaterally affected patients with sporadic R and patients with unilateral sporadic R with more than one primary tumor have to be regarded as germ cell mutants; they will transmit the gene to 50% of their offspring. Only 10%-12% of unilateral sporadic cases are germ cell mutants; 88%-90% are nonhereditary; in these cases the tumor is probably caused by a somatic mutation. 5) In a minority of cases, deletion of the chromosome segment 13q14(=intersitital deletion of the long arm of chromosome 13) has been observed. In addition to R, the patients show a variable degree of general or mental retardation; often there are few external indications of a chromosome aberration. Other chromosome studies suggest anomalies of chromosome 13 in tumor tissue even in cases not showing an anomaly of this chromosome in blood cultures, and possibly a slightly increased chromosome instability. 6) Patients with bilateral, and possibly in general with hereditary, R run an increased risk of becoming affected with other tumor diseases, such as osseous sarcomas, in later life. 7) Knudson's hypothesis of two mutational steps leading to both the hereditary and the nonhereditary variants of R is discussed critically, and the alternative possibility is suggested that in the nonhereditary variant a single mutational step--possibly a small chromosome aberration--could be enough to produce a tumor. 8) Evidence indicating a possible viral origin of R is cited, and animal experiments are mentioned in which R-like tumors have successfully been produced by local DNA virus inoculation. 9) As a consequence of improved survival and reproduction of R patients, an increased in the incidence of R and in the proportion of bilateral cases among all R patients must be anticipated. 10) Detailed rules for genetic counseling in families affected by R are given.
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PMID:Genetics of retinoblastoma. 39 14

We have previously shown that human piebaldism results from mutations of the KIT gene, which encodes the receptor for the mast/stem cell growth factor and is located in chromosome segment 4q12. Using DNA of a patient with piebaldism, mental retardation, and multiple congenital anomalies associated with a 46,XY,del(4) (q12q21.1) karyotype, we carried out quantitative Southern blot hybridization analyses of the KIT gene and the adjacent PDGFRA (platelet-derived growth factor receptor alpha subunit) genes. The patient was hemizygous for both the KIT and PDGFRA genes, indicating that both of these genes are included within the deleted region. Therefore, deletion of the KIT and PDGFRA genes may account for the piebald phenotype in this patient.
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PMID:Deletion of the KIT and PDGFRA genes in a patient with piebaldism. 127 71

A new fragile site (FRAXE) in Xq28 is described. It appears to be a typical folate sensitive fragile site. The fragile site is not associated with mental retardation, it does not give abnormal results when subjected to Southern analysis with probe pfxa3 which detects the unstable DNA sequence characteristic of fragile X syndrome. In situ hybridization mapping locates the fragile site between 150 kb and 600 kb distal to FRAXA. The distinction between the two fragile sites is important clinically since cytogenetic detection of FRAXE, without molecular analysis, could result in misdiagnosis of fragile X syndrome.
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PMID:Characterisation of a new rare fragile site easily confused with the fragile X. 130 Nov 46

Norrie disease is a human X-linked recessive disorder of unknown etiology characterized by congenital blindness, sensory neural deafness and mental retardation. This disease gene was previously linked to the DXS7 (L1.28) locus and the MAO genes in band Xp11.3. We report here fine physical mapping of the obligate region containing the Norrie disease gene (NDP) defined by a recombination and by the smallest submicroscopic chromosomal deletion associated with Norrie disease identified to date. Analysis, using in addition two overlapping YAC clones from this region, allowed orientation of the MAOA and MAOB genes in a 5'-3'-3'-5' configuration. A recombination event between a (GT)n polymorphism in intron 2 of the MAOB gene and the NDP locus, in a family previously reported to have a recombination between DXS7 and NDP, delineates a flanking marker telomeric to this disease gene. An anonymous DNA probe, dc12, present in one of the YACs and in a patient with a submicroscopic deletion which includes MAOA and MAOB but not L1.28, serves as a flanking marker centromeric to the disease gene. An Alu-PCR fragment from the right arm of the MAO YAC (YMAO.AluR) is not deleted in this patient and also delineates the centromeric extent of the obligate disease region. The apparent order of these loci is telomere ... DXS7-MAOA-MAOB-NDP-dc12-YMAO.AluR ... centromere. Together these data define the obligate region containing the NDP gene to a chromosomal segment less than 150 kb.
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PMID:The Norrie disease gene maps to a 150 kb region on chromosome Xp11.3. 130 Nov 61

The fragile-X syndrome of mental retardation is associated with an expansion in the number of CGG repeats present in the FMR1 gene. The repeat region is within sequences characteristic of a CpG island. Methylation of CpG dinucleotides that are 5' to the CGG repeat has been shown to occur on the inactive X chromosome of normal females and on the X chromosome of affected fragile-X males, and is correlated with silencing of the FMR1 gene. The methylation status of CpG sites 3' to the repeat and within the repeat itself has not previously been reported. We have used two methylation-sensitive restriction enzymes, AciI and Fnu4HI, to further characterize the methylation pattern of the FMR1 CpG island in normal individuals and in those carrying fragile-X mutations. Our results indicate that: (i) CpG dinucleotides on the 3' side of the CGG repeat are part of the CpG island that is methylated during inactivation of a normal X chromosome in females; (ii) the CGG repeats are also part of the CpG island and are extensively methylated as a result of normal X-chromosome inactivation; (iii) similar to normal males, unaffected fragile-X males with small CGG expansions are unmethylated in the CpG island; for affected males, the patterns of methylation are similar to those of a normal, inactive X chromosome; (iv) in contrast to the partial methylation observed for certain sites in lymphocyte DNA, complete methylation was observed in DNA from cell lines containing either a normal inactive X chromosome or a fragile-X chromosome from an affected male.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Methylation analysis of CGG sites in the CpG island of the human FMR1 gene. 130 Nov 65

Fragile X syndrome is the most frequent form of inherited mental retardation and is associated with a fragile site at Xq27-3. This fragile site is an unstable microsatellite repeat, p(CCG). In fragile X syndrome families, this sequence exhibits variable amplification, the length of which correlates with phenotype. Affected persons have both a "full mutation" and abnormal DNA methylation. Subjects with smaller increase of this sequence, called "premutation", have little or no risk retardation, but are at high risk of having affected children or grandchildren. The passage from "premutation" to "full mutation" status occurs only with transmission from the mother. The unusual segregation patterns in fragile X pedigrees is referred to as the Sherman paradox, now elucidated by genotypic analysis. We present here a brief review of this pathology and illustrate the use of this new diagnostic test in our laboratory.
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PMID:[Pathology of unstable sequence of genome: fragile-X-syndrome]. 130 Dec 24

Fragile X syndrome is the most frequent form of inherited mental retardation and segregates as an X-linked dominant with reduced penetrance. Recently, we have identified the FMR-1 gene at the fragile X locus. Two molecular differences of the FMR-1 gene have been found in fragile X patients: a size increase of an FMR-1 exon containing a CGG repeat and abnormal methylation of a CpG island 250 bp proximal to this repeat. Penetrant fragile X males who exhibit these changes typically show repression of FMR-1 transcription and the presumptive absence of FMR-1 protein is believed to contribute to the fragile X phenotype. It is unclear, however, if either or both molecular differences in FMR-1 gene is responsible for transcriptional silencing. We report here the prenatal diagnosis of a male fetus with fragile X syndrome by utilizing these molecular differences and show that while the expanded CGG-repeat mutation is observed in both the chorionic villi and fetus, the methylation of the CpG island is limited to the fetal DNA (as assessed by BssHII digestion). We further demonstrate that FMR-1 gene expression is repressed in the fetal tissue, as is characteristic of penetrant males, while the undermethylated chorionic villi expressed FMR-1. Since the genetic background of the tissues studied is identical, including the fragile X chromosome, these data indicate that the abnormal methylation of the FMR-1 CpG-island is responsible for the absence of FMR-1 transcription and suggests that the methylation may be acquired early in embryogenesis.
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PMID:DNA methylation represses FMR-1 transcription in fragile X syndrome. 130 13

Interest in the human cytomegalovirus (HCMV) mainly derives from its associations with congenital malformations, mental retardation, and severe or fatal infections in immunosuppressed individuals such as transplant patients, tumor and AIDS patients. It is evidenced that there has been a need for a rapid and sensitive methods to detect an ongoing acute infection. The recent studies showed that high titers of antibody to the glycoprotein 52kd are present in sera of patients undergoing acute HCMV infection. However, purification of individual glycoprotein from HCMV-infected cells is a daunting prospect. HCMV glycoprotein 52 kd expressed via recombinant DNA techniques are a promising approach to solve this problem. In order to evaluate the diagnostic value of the recombinant glycoprotein 52 kd antigenic code region for HCMV infection, we have used the polymerase chain reaction (PCR) and recombinant DNA techniques to construct successfully the high-level expression plasmid pHCMV containing the HCMV GP-52 kd antigenic code region, with the predicted protein at levels up to 20% in total bacterial protein. The expressed protein was purified from SDS-PAGE, used as an antigen in Western-blot, and reacted with 12 cases of the positive sera, 4 cases of the negative sera, following by reaction with HRP-labelled horse IgG antibody against human. The results indicated that the approach we are using to detect antibody to HCMV acute infection are as sensitive as general serological methods such as ELISA, with the advantages of easy preparation of antigen with high quantity, and clinical practicability.
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PMID:[Preliminary use of recombinant glycoprotein 52kd as an antigen in the diagnosis of human cytomegalovirus infection]. 132 25

Fragile-X syndrome is a major cause of mental retardation in humans. The X-inactivation imprinting model accounts for the unusual pattern of inheritance and expression of this syndrome. According to this model, the fragile-X mutation creates a local block to the attempted reactivation of the mutant X chromosome prior to oogenesis. This local block results in an "imprinted" fragile-X chromosome that is deleterious in males and in females for whom this chromosome is predominantly the active X chromosome. The imprinted state of the fragile-X mutation is inferred to be stable when transmitted by an imprinted female because the penetrance of the syndrome in sons of affected females is estimated to be 1.0. To provide a more precise estimate of the stability of the proposed fragile-X imprint, we have analyzed published pedigrees that include restriction fragment length polymorphism and cytogenetic data from sibships with mothers who are interpreted as having an imprinted fragile-X allele. We conclude that the fragile-X imprint was stable in 46 out of 48 female meioses. This analysis leads to a preliminary estimate of about 96% for the stability of the imprint through female meiosis. Two imprinted females had progeny who appeared to be carriers of a nonimprinted fragile-X allele. If this interpretation is correct, then reversion from the imprinted to the nonimprinted state, or "erasure," can occasionally occur when the mutant fragile-X allele is transmitted by an imprinted female. We discuss the genetic and epigenetic significance of possible female erasure. We request DNA and cytogenetic information from unpublished pedigrees to quantify further the stability, during female meiosis, of the proposed imprinted state of the mutant fragile-X allele.
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PMID:Estimating the stability of the proposed imprinted state of the fragile-X mutation when transmitted by females. 134 87


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