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 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 oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked multisystem disorder with major abnormalities of eyes, nervous system, and kidneys. Clinical manifestations include congenital cataract, mental retardation, and renal tubular dysfunction. A gene (OCRL1) responsible for OCRL was identified by positional cloning and its product OCRL-1 protein was shown to be a phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] 5-phosphatase localized to the Golgi apparatus. We describe three mutations in OCRL1, one in a patient with severe phenotype and two in patients with moderate phenotype (degree of mental retardation and musculoskeletal abnormalities). The patient with severe phenotype had a G-to-A transition at nucleotide (nt) 1,739, causing an Arg-to-Gln substitution at amino acid 577, and one patient with moderate phenotype had a C-to-G transversion at nt 1,812, leading to a His-to-Gln substitution at amino acid 601. Both Arg-577 and His-601 are encoded by exon 15 and are probably important for proper function of this protein, since these are conserved in various enzymes catalyzing dephosphorylation of inositol compounds. In the other patient with the moderate phenotype, there was a G-to-A transition at nt 2,797 located at the 3'-end of exon 22. This substitution led to a skip of the same exon as well as conversion of codon-930 from GCT (Ala) to ACT (Thr) in the normal-size transcript. When we measured the enzyme activity in skin fibroblasts from the three patients, the activity was less than 10%, compared to findings in normal controls. Western blot analysis showed absence or severe decrease in OCRL-1 protein in cell lysates derived from these patients.
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PMID:Oculocerebrorenal syndrome of Lowe: three mutations in the OCRL1 gene derived from three patients with different phenotypes. 963 63

The Wilms' tumor gene (WT1) encodes a zinc-finger transcription factor involved in the development of the kidneys and gonads and their subsequent normal function. Mutations in the WT1 gene were identified in patients with WAGR (Wilms' tumor, aniridria, genitourinary abnormalities, and mental retardation), Denys-Drash syndrome, and Frasier syndrome (FS). Constitutional heterozygous mutations of the WT1 gene, almost all located at intron 9, are found in patients with FS. This syndrome is characterized by female external genitalia in 46,XY patients, late renal failure, streak gonads, and high risk of gonadoblastoma development. We report a male with FS with an unusual phenotype characterized by normal penis size with perineal hypospadias, end-stage renal failure at the age of 19 yr, normal adult male serum T levels, extremely elevated gonadotropin levels, para-testicular leiomyoma, unilateral testicular germ cell tumor, bilateral gonadoblastoma, and absence of gonadal dysgenesis. Automatic sequencing identified the IVS9 +4C>T mutation in the WT1 gene, which predicts a change in splice site utilization. WT1 transcript analysis showed reversal of the normal positive/negative KTS (lysine, threonine, and serine) isoform ratio, confirming the diagnosis of FS. This patient with FS presents an external genitalia of Denys-Drash syndrome, suggesting that these two syndromes are not distinct diseases but may represent two ends of a spectrum of disorders caused by alterations in WT1 gene. This case expands the spectrum of phenotypes associated with WT1 mutations, by including predominantly male ambiguous genitalia and absence of gonadal dysgenesis, extremely high gonadotropin levels, and delayed adrenarche, and presence of a para-testicular leiomyoma, bilateral gonadoblastoma, and germ cell neoplasia.
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PMID:An unusual phenotype of Frasier syndrome due to IVS9 +4C>T mutation in the WT1 gene: predominantly male ambiguous genitalia and absence of gonadal dysgenesis. 1205 Feb 5

A 19-year-old man with mild mental retardation was diagnosed as having metastatic choriocarcinoma and a testicular tumor. Histopathological examination of the resected testis revealed the presence of a small lesion of mature teratoma but no trace of choriocarcinoma. The remaining seminiferous tubules were atrophic and lined by large atypical germ cells, which were diagnosed as intratubular germ cell neoplasia of the unclassified type (IGCNU). A small area with prominent tubules was also observed. Within this lesion, the tubules were dilated and contained several layers of cells with central necrosis. Immunohistological comparison of staining for several biological markers (Ki-67, c-kit and placental alkaline phosphatase) between cells in the atrophic tubules and those in the dilated tubules indicated a progression of the latter cells to cells with a more proliferative ability. In the opposite testis, examined at autopsy after death due to metastatic choriocarcinoma, all seminiferous tubules were lined by Sertoli cells only. It was therefore assumed that the germ cell tumor of the combined histological type had primarily arisen in the background of IGCNU, and that choriocarcinoma had spontaneously regressed. The early onset of these testicular neoplastic lesions strongly indicates their occurrence under the genetic background of gonadal dysplasia, the Sertoli cell-only syndrome. The possible relation of gonadal disease to mental retardation in this patient is also discussed.
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PMID:Intratubular germ cell neoplasia of unclassified type occupying the whole testis accompanied by a small mature teratoma and metastatic choriocarcinoma and Sertoli cell-only tubules in the other testis. 1451 26

We report a case of a patient who presented with anterior mediastinal mass, seizure disorder, and mental retardation. Computerized tomography-guided fine-needle aspiration biopsy of the mass showed nonseminomatous germ cell tumor. Chromosomal analysis showed XXY karyotype. A diagnosis of Klinefelter syndrome and mediastinal germ cell tumor was made.
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PMID:Nonseminomatous germ cell tumor with seizure disorder and mental retardation. 2053 99