Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gene mapping data indicate that the human X chromosome is enriched in genes that affect both, higher cognitive efficiency and reproductive success. This raises the question whether these functions are ancient, or whether conserved X-linked genes were recruited to new functions. We have studied three X-linked mental retardation (XLMR) genes by RNA in situ hybridization in mouse and in chicken, in which these genes are autosomal: Rho guanine nucleotide exchange factor 6 (ARHGEF6), oligophrenin (OPHN1), and p21 activated kinase 3 (PAK3). In the mouse these genes are specifically expressed in telencephalic regions. Their orthologues in the chicken gave patterns of similar specificity in ancient parts of the brain, i.e. cerebellum and mesencephalon, but were not expressed in the telencephalon. Also in the testes, specific expression was only found in mouse, not in chicken. These data are interpreted such that certain genes on the X chromosome gained novel functions during evolution.
 ...
PMID:Recruitment of old genes to new functions: evidences obtained by comparing the orthologues of human XLMR genes in mouse and chicken. 1731 56

A tiling X-chromosome-specific genomic array with a theoretical resolution of 80 kb was developed to screen patients with idiopathic mental retardation (MR) for submicroscopic copy number differences. Four patients with aberrations previously detected at lower resolution were first analyzed. This facilitated delineation of the location and extent of the aberration at high resolution and subsequently, more precise genotype-phenotype analyses. A cohort of 108 patients was screened, 57 of which were suspected of X-linked mental retardation (XLMR), 26 were probands of brother pairs, and 25 were sporadic cases. A total of 15 copy number changes in 14 patients (13%) were detected, which included two deletions and 13 duplications ranging from 0.1 to 2.7 Mb. The aberrations are associated with the phenotype in five patients (4.6%), based on the following criteria: de novo aberration; involvement of a known or candidate X-linked nonsyndromic(syndromic) MR (MRX(S)) gene; segregation with the disease in the family; absence in control individuals; and skewed X-inactivation in carrier females. These include deletions that contain the MRX(S) genes CDKL5, OPHN1, and CASK, and duplications harboring CDKL5, NXF5, MECP2, and GDI1. In addition, seven imbalances were apparent novel polymorphic regions because they do not fulfill the proposed criteria. Taken together, our data strongly suggest that not only deletions but also duplications on the X chromosome contribute to the phenotype more often than expected, supporting the increased gene dosage mechanism for deregulation of normal cognitive development.
 ...
PMID:Detection of genomic copy number changes in patients with idiopathic mental retardation by high-resolution X-array-CGH: important role for increased gene dosage of XLMR genes. 1754 40

Craniofrontonasal syndrome (CFNS [MIM 304110]) is an X-linked malformation syndrome characterized by craniofrontonasal dysplasia and extracranial manifestations in heterozygous females. In the majority of patients CFNS is caused by mutations in the EFNB1 gene (MIM 300035). We identified three girls with classical CFNS and mild developmental delay harboring de novo deletions of the EFNB1 gene. Applying haplotype analysis, Southern blot hybridization and array-comparative genomic hybridization, deletion of EFNB1 was found to be part of contiguous gene deletions in the patients. In one patient the deletion interval includes the genes for oligophrenin-1 (OPHN1 [MIM 300127]) and praja 1 (PJA1 [MIM 300420]). In the second patient the deletion includes OPHN1, PJA1 and the gene for ectodysplasin A (EDA [MIM 300451]). In the third patient EFNB1 gene deletion may include deletion of regulatory regions 5' of OPHN1. Previously, the OPHN1 gene has been shown to be responsible for recessive X-linked mental retardation. Although it is too early to predict the future cognitive performance of the two infant patients with contiguous gene deletions of OPHN1-EFNB1-PJA1, mild learning disabilities have been recognized in the older, third patient. It is important for genetic counseling to be aware that their male offspring may not only be carriers of CFNS but may also be affected by mental retardation and anhidrotic ectodermal dysplasia.
 ...
PMID:Contiguous gene deletions involving EFNB1, OPHN1, PJA1 and EDA in patients with craniofrontonasal syndrome. 1794 86

OPHN1 mutations cause a syndromic form of mental retardation (MR) characterized by cerebellar hypoplasia, early hypotonia, motor and speech delay, with occasional seizures and strabismus. Here we report on a familial chromosome duplication spanning about 800 Kb of Xq12q13.1, associated with MR and a distinctive phenotype in the affected male, but not in his heterozygous mother. The parents were healthy and non-consanguineous with a history of three pregnancies. The first resulted in the birth of a boy with MR, motor impairment and seizures. The second pregnancy was terminated because of trisomy 18. At the time of the third, the first affected boy was analyzed by array-CGH, which revealed a 800 Kb duplication at Xq12q13.1, encompassing three genes, including OPHN1. This mutation was inherited from his healthy mother and was not present in any of the three maternal brothers. To our knowledge this is the first report of a clinical phenotype associated with duplication of Xq12q13.
 ...
PMID:Association of syndromic mental retardation with an Xq12q13.1 duplication encompassing the oligophrenin 1 gene. 1851 29

The OPHN1 gene encodes a Rho-GTPase activating protein (RhoGAP), and mutations in OPHN1 are responsible for non-specific X-linked mental retardation (NSMR). A SNP located in the 5'-untranslated region (UTRs) of OPHN1 (rs492933) was examined by PCR-RFLP to assess its contribution to cognitive ability in 234 unrelated healthy and MR children in the Qinba Mountain region in Shaanxi. The allelic frequencies of rs492933 were 0.826 for the C allele and 0.174 for the T allele. Genotype frequencies and allelic frequencies were not significantly different between the MR and the controls, or between the borderline group and the controls. In conclusion, there is no association between the OPHN1 gene polymorphism and NSMR in the Qinba Mountain region children.
 ...
PMID:[Anassociation study between OPHN1 gene rs492933 polymorphism and mental retardation in children of the Qinba Mountain region.]. 1893 Aug 91

The high concordance for autism symptoms in monozygotic twin-pairs compared to di-zygotic twins and/or non-twin sib-ships suggests a high genetic determinism in autism. Those results have hypothesized multi-factorial determinism in accordance with family studies and mathematical models. However, linkage and association or candidate gene strategies have failed to-date to identify clearly involved mechanisms. Mental retardation (MR) is known as frequently associated to autism. Multiplex XLMR pedigrees have been reported with only one mutated patient having autism and MR: different X-located MR genes have been shown to be involved (NLGN4, MECP2, OPHN1, ZNF674 and FRAXA) which does not suggest that they could be "autism genes". Tuberous sclerosis studies and report of numerous autosomal domains shown deleted in MR-autistic subjects suggest that several autosomal dominant (AD) genes could be also involved in MR with autism. Whereas multiplex AD-MR families are rare, AD de novo mutations could explain numerous sporadic situations of non-specific MR and of autism with MR, in accordance with twin studies. Finally, we hypothesize that in those autistic subjects with mendelian MR, the XL-MR or AD-MR gene (G1) would pave the way for a second Mendelian factor (G2) responsible for autism symptoms.
 ...
PMID:Could autism with mental retardation result from digenism and frequent de novo mutations? 1916 Jan 28

We observed a three-generation family with two maternal cousins and an uncle affected by mental retardation (MR) with cerebellar hypoplasia. X-linked inheritance and the presence of cerebellar malformation suggested a mutation in the OPHN1 gene. In fact, mutational screening revealed a 2-bp deletion that abolishes a donor splicing site, resulting in the inclusion of the initial 48 nucleotides of intron 7 in the mRNA. This mutation determines the production of a mutant oligophrenin 1 protein with 16 extra amino acids inserted in-frame in the N-terminal BAR (Bin1/amphiphysin/Rvs167) domain. This is the first case of a mutation in OPHN1 that does not result in the production of a truncated protein or in its complete loss. OPHN1 (ARHGAP41) encodes a GTPase-activating (GAP) protein belonging to the GRAF subfamily characterized by an N-terminal BAR domain, followed by a pleckstrin-homology (PH) domain and the GAP domain. GRAF proteins play a role in endocytosis and are supposed to dimerize via their BAR domain, that induces membrane curvature. The extra 16 amino acids cause the insertion of 4.4 turns in the third alpha-helix of the BAR domain and apparently impair the protein function. In fact, the clinical phenotype of these patients is identical to that of patients with loss-of-function mutations.
 ...
PMID:Insertion of 16 amino acids in the BAR domain of the oligophrenin 1 protein causes mental retardation and cerebellar hypoplasia in an Italian family. 2179 28

We report the case of a 33-year-old pregnant woman. The third-trimester ultrasound scan during pregnancy revealed fetal bilateral ventricular dilatation, macrosomia and a transverse diameter of the cerebellum at the 30th centile. A brain MRI scan at 31 weeks of gestation led to a diagnosis of hypoplasia of the cerebellar vermis without hemisphere abnormalities and a non compressive expansion of the cisterna magna. The fetal karyotype was 46,XX. The pregnancy was terminated and array-CGH analysis of the fetus identified a 238 kb de novo deletion on chromosome Xp12, encompassing part of OPHN1 gene. Further studies revealed a completely skewed pattern of X inactivation. OPHN1 is involved in X-linked mental retardation (XLMR) with cerebellar hypoplasia and encodes a Rho-GTPase-activating protein called oligophrenin-1, which is produced throughout the developing mouse brain and in the hippocampus and Purkinje cells of the cerebellum in adult mice. Neuropathological examination of the female fetus revealed cerebellar hypoplasia and the heterotopia of Purkinje cells at multiple sites in the white matter of the cerebellum. This condition mostly affects male fetuses in humans. We report here the first case of a de novo partial deletion of OPHN1, with radiological and neuropathological examination, in a female fetus.
 ...
PMID:Neuropathological features in a female fetus with OPHN1 deletion and cerebellar hypoplasia. 2341 24

An elevated odds ratio for low IQ has been found for cryptorchid boys. Furthermore, poor school performance has been observed in cryptorchid boys with impaired mini-puberty. Gene expression analysis, qPCR and immunohistology were performed on testicular biopsies from 7 boys who underwent orchiopexy and had testicular histology typical of a high risk of infertility (HIR). The results were compared with 12 biopsies from cryptorchid boys with a low risk for developing infertility. The following genes associated with mental retardation were identically expressed: GDI1, OPHN1, PAK3, ARHGEF6, IL1RAPL, ACSL4, MECP2, RPS6KA3, ARX, and ATRX. However, boys in the HIR group had low or no expression of EGR4, FMR2 (AFF2) and VCX3A. In conclusion, impaired expression of genes known to encode proteins involved in signaling pathways that regulate cytoskeletal organization, synaptic vesicle transport and the establishment of connections between neuronal cells may contribute to reduced intellectual and cognitive functioning in infertile cryptorchid males.
...
PMID:Decreased expression of genes associated with memory and x-linked mental retardation in boys with non-syndromic cryptorchidism and high infertility risk. 2471 54


<< Previous 1 2