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)

RING-finger proteins contain cysteine-rich, zinc-binding domains and are involved in the formation of macromolecular scaffolds important for transcriptional repression and ubiquitination. In this study, we have identified a RING-H2 finger gene, PJA1 (for praja-1), from a human brain cDNA library and mapped it to human chromosome Xq12 between markers DXS983 and DXS1216, a region implicated in X-linked mental retardation (MRX). Northern blot analysis indicated a 2.7-kb transcript that was abundantly expressed in the brain, including regions of the cerebellum, cerebral cortex, medulla, occipital pole, frontal lobe, temporal lobe, and putamen. Amino acid sequence analysis of the 71-kDa protein PJA1 showed 52.3% identity to human PJA2 (for praja-2, also known as NEURODAP1/KIAA0438) and also a significant identity to its homologs in rat, mouse, and zebrafish. In vitro binding and immunoprecipitation assays demonstrated that both PJA1 and PJA2 are able to bind the ubiquitin-conjugating enzyme UbcH5B. Moreover, the ubiquitination assay indicated that PJA1 and PJA2 have an E2-dependent E3 ubiquitin ligase activity. Thus our findings demonstrate that PJA1 can be involved in protein ubiquitination in the brain and is a suitable candidate gene for MRX.
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PMID:PJA1, encoding a RING-H2 finger ubiquitin ligase, is a novel human X chromosome gene abundantly expressed in brain. 1203 2

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

Nonsyndromic X-linked mental retardation (MRX) is defined by an X-linked inheritance pattern of low IQ, problems with adaptive behavior, and the absence of additional specific clinical features. The 13 MRX genes identified to date account for less than one-fifth of all MRX, suggesting that numerous gene defects cause the disorder in other families. In a female patient with severe nonsyndromic mental retardation and a de novo balanced translocation t(X;7)(p11.3;q11.21), we have cloned the DNA fragment that contains the X-chromosomal and the autosomal breakpoint. In silico sequence analysis provided no indication of a causative role for the chromosome 7 breakpoint in mental retardation (MR), whereas, on the X chromosome, a zinc-finger gene, ZNF41, was found to be disrupted. Expression studies indicated that ZNF41 transcripts are absent in the patient cell line, suggesting that the mental disorder in this patient results from loss of functional ZNF41. Moreover, screening of a panel of patients with MRX led to the identification of two other ZNF41 mutations that were not found in healthy control individuals. A proline-to-leucine amino acid exchange is present in affected members of one family with MRX. A second family carries an intronic splice-site mutation that results in loss of specific ZNF41 splice variants. Wild-type ZNF41 contains a highly conserved transcriptional repressor domain that is linked to mechanisms of chromatin remodeling, a process that is defective in various other forms of MR. Our results suggest that ZNF41 is critical for cognitive development; further studies aim to elucidate the specific mechanisms by which ZNF41 alterations lead to MR.
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PMID:Mutations in the ZNF41 gene are associated with cognitive deficits: identification of a new candidate for X-linked mental retardation. 1462 91

Deletions of the 1q telomere have been reported in several studies screening for subtelomeric rearrangements. However, an adequate clinical description is available from only a few patients. We provide a clinical description of a patient with a subtelomeric deletion of chromosome 1q, previously detected by us in a screening study. Comparison of the clinical presentation of our patient with rare cases reported previously provides further evidence for a specific phenotype of 1q patients, including mental retardation, growth retardation, sometimes with prenatal onset, progressive microcephaly, seizures, hand and foot abnormalities and a variety of midline defects, including corpus callosum, cardiac, genital and gastro-esophageal abnormalities. This clinical presentation is reminiscent of that of patients with larger, microscopically visible deletions of chromosome 1q (>3 Mb) characterized by growth and mental retardation, coarse faces with thin upper lip, epilepsy, and variable other anomalies. In addition, the breakpoint region was mapped to a 26 kb region within the RGS7 gene. Among the 17 known genes in the candidate region, are zinc-finger genes. Other members of this gene family have been implicated in different forms of mental retardation.
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PMID:Clinical report of a pure subtelomeric 1qter deletion in a boy with mental retardation and multiple anomalies adds further evidence for a specific phenotype. 1582 26

X-linked mental retardation (XLMR) affects one in 600 males and is highly heterogeneous. We describe here a 29-year-old woman with severe nonsyndromic mental retardation and a balanced reciprocal translocation between chromosomes X and 15 [46,XX,t(X;15)(q13.3;cen)]. Methylation studies showed a 100% skewed X-inactivation in patient-derived lymphocytes indicating that the normal chromosome X is retained inactive. Physical mapping of the breakpoints localised the Xq13.3 breakpoint to within 3.9 kb of the first exon of the ZDHHC15 gene encoding a zinc-finger and a DHHC domain containing product. Expression analysis revealed that different transcript variants of the gene are expressed in brain. ZDHHC15-specific RT-PCR analysis on lymphocytes from the patient revealed an absence of ZDHHC15 transcript variants, detected in control samples. We suggest that the absence of the ZDHHC15 transcripts in this patient contributes to her phenotype, and that the gene is a strong candidate for nonsyndromic XLMR.
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PMID:Loss of ZDHHC15 expression in a woman with a balanced translocation t(X;15)(q13.3;cen) and severe mental retardation. 1591 61

Array-based comparative genomic hybridization has proven to be successful in the identification of genetic defects in disorders involving mental retardation. Here, we studied a patient with learning disabilities, retinal dystrophy, and short stature. The family history was suggestive of an X-linked contiguous gene syndrome. Hybridization of full-coverage X-chromosomal bacterial artificial chromosome arrays revealed a deletion of ~1 Mb in Xp11.3, which harbors RP2, SLC9A7, CHST7, and two hypothetical zinc-finger genes, ZNF673 and ZNF674. These genes were analyzed in 28 families with nonsyndromic X-linked mental retardation (XLMR) that show linkage to Xp11.3; the analysis revealed a nonsense mutation, p.E118X, in the coding sequence of ZNF674 in one family. This mutation is predicted to result in a truncated protein containing the Kruppel-associated box domains but lacking the zinc-finger domains, which are crucial for DNA binding. We characterized the complete ZNF674 gene structure and subsequently tested an additional 306 patients with XLMR for mutations by direct sequencing. Two amino acid substitutions, p.T343M and p.P412L, were identified that were not found in unaffected individuals. The proline at position 412 is conserved between species and is predicted by molecular modeling to reduce the DNA-binding properties of ZNF674. The p.T343M transition is probably a polymorphism, because the homologous ZNF674 gene in chimpanzee has a methionine at that position. ZNF674 belongs to a cluster of seven highly related zinc-finger genes in Xp11, two of which (ZNF41 and ZNF81) were implicated previously in XLMR. Identification of ZNF674 as the third XLMR gene in this cluster may indicate a common role for these zinc-finger genes that is crucial to human cognitive functioning.
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PMID:ZNF674: a new kruppel-associated box-containing zinc-finger gene involved in nonsyndromic X-linked mental retardation. 1638 66

Rett syndrome (RTT; OMIM 312750) is an X-linked dominant neurological disorder, which affects mostly females. It is associated with mutations of the MECP2 gene, codifying for a methyl-CpG DNA binding protein of the MBDs family, sharing the common Methyl Binding Domain. MeCP2 binds single methylated CpG pair and brings transcriptional silencing to the substrate DNA templates. However, around 5-10% of clinically well defined RTT patients do not show any mutations in this gene. Several hypotheses have been postulated to clarify the remaining unexplained RTT cases. We pointed our attention on Kaiso gene. This gene is localized in the Xq23 region and codifies for a protein acting as a methyl-CpG binding protein by using three zinc-finger domains: for this reason it is not strictly related to the MBD family of proteins, even if it may repress transcription of methylated genes as well. To investigate the potential association of Kaiso disfunction with pathogenesis of Rett syndrome, we approached the analysis at two different levels. Primarily, we performed an itemized murine brain expression analysis of Kaiso gene. Expression data and localization made it an excellent candidate as additional causative gene for MECP2 negative, classical RTT patients. On the bases of this data a detailed mutational analysis of 44 patients from Spanish, UK, and Italian archives has been performed to the coding region of Kaiso. No mutation was found while a very frequent polymorphism was identified and characterized. Our study suggests that this gene is not implicated in the RTT molecular pathogenesis, but additional analyses are needed to exclude it as causative gene for X-linked mental retardation disorders.
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PMID:The X-linked methyl binding protein gene Kaiso is highly expressed in brain but is not mutated in Rett syndrome patients. 1653 Sep 85

Neuronal-glial communication is essential for constructing the orthogonal axon scaffold in the developing Drosophila central nervous system (CNS). Longitudinal glia (LG) guide extending commissural and longitudinal axons while pioneer and commissural neurons maintain glial survival and positioning. However, the transcriptional regulatory mechanisms controlling these processes are not known. Previous studies showed that the midline function of the jing C2H2-type zinc-finger transcription factor was only partially required for axon scaffold formation in the Drosophila CNS. We therefore screened for gain-of-function enhancers of jing gain of function in the eye and identified the Drosophila homolog of the disease gene of human alpha-thalassemia/mental retardation X-linked (ATR-X) as well as other genes with potential roles in gene expression, translation, synaptic transmission, and cell cycle. jing and DATR-X reporter genes are expressed in both CNS neurons and glia, including the LG. Coexpression of jing and DATR-X in embryonic neurons synergistically affects longitudinal connective formation. During embryogenesis, jing and DATR-X have autonomous and nonautonomous roles in the lateral positioning of LG, neurons, and longitudinal axons as shown by cell-specific knockdown of gene expression. jing and DATR-X are also required autonomously for glial survival. jing and DATR-X mutations show synergistic effects during longitudinal axon formation suggesting that they are functionally related. These observations support a model in which downstream gene expression controlled by a potential DATR-X-Jing complex facilitates cellular positioning and axon guidance, ultimately allowing for proper connectivity in the developing Drosophila CNS.
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PMID:Glial and neuronal functions of the Drosophila homolog of the human SWI/SNF gene ATR-X (DATR-X) and the jing zinc-finger gene specify the lateral positioning of longitudinal glia and axons. 1664 85

Carbonic anhydrase II (CA II) is one of 14 isozymes of carbonic anhydrases, zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide to bicarbonate. Mutations in CA II in humans lead to osteopetrosis with renal tubular acidosis and cerebral calcifications, a disorder often associated with mental retardation. Recently, new avenues in CA II research have opened as a result of discoveries that the enzyme increases bicarbonate and proton fluxes and may play an important role in brain tissue. In the human brain, CA II was localized to oligodendrocytes, myelin, and choroid plexus epithelium. Because this conclusion was based on a few fragmentary reports, we analyzed in more detail the expression of the enzyme in human telencephalon. By immunoblotting, we found a gradual increase in CA II levels from 17 weeks' gestation to childhood and adolescence. By immunohistochemistry, CA II was found to be present not only in oligodendrocytes and choroid plexus epithelium (declining with aging in both these locations), but also in a subset of neurons mostly with GABAergic phenotype, in a few astrocytes, and transiently during brain development in the endothelial cells of microvessels. The enzyme also occurred in oligodendrocyte processes in contact with myelinating axons, myelin sheaths, and axolemma, but was either absent or appeared in minute amounts in compact myelin. These findings suggest the possible involvement of CA II in a wide spectrum of biologic processes in the developing and adult human brain and may contribute to better understanding of the pathogenesis of cerebral calcifications and mental retardation caused by CA II deficiency.
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PMID:Carbonic anhydrase II in the developing and adult human brain. 1682 53

The present study was undertaken to evaluate the nutritional status of children with special needs in Alexandria city, on the basis of nutrient intake and food consumption. Socio-demographic characteristics and dietary data were determined in a sample of 231 disabled children chosen randomly from five specialized day care centers. Results showed that the age of the sample ranged from less than 7 to 24 years with a mean age of 12.6 +/- 4.7 years. Mental retardation represents the highest proportion of subjects followed by Down's syndrome and then Autism Male subjects were found to consume higher nutrients than females at all ages except age under seven years. The intake of both gender was less than the recommended for energy, calcium, vitamin A, niacin and zinc. While the intake of protein and vitamin C was more than the RDA Iron intake was below the recommended for females at all ages and within the acceptable level for male. The results also showed that there is a relationship between nutrient intake and disability type. Down syndrome children were found to consume more nutrients than mentally retarded and autistic subjects.
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PMID:Assessment of the nutritional status of children with special needs in Alexandria: I. Nutrient intake and food consumption. 1691 48


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