Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917816 (mental retardation)
 15,867 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report here the first case of an L1CAM gene mutation identified in mental retardation, adducted thumbs, shuffling gait, and aphasia (MASA) syndrome in Japan. The patient was a 10-year-old boy with mild mental retardation, bilateral adducted thumbs and corpus callosum hypoplasia. His family had no history of MASA syndrome. The L1CAM gene contained a nonsense mutation (R1166X) in exon 26 in the cytoplasmic domain. No mutation was found in the extracellular and transmembrane domains of L1CAM. The abnormal development of axon tracts resulting in the corpus callosum hypoplasia and adducted thumbs appears to be caused by malfunction of the cytoplasmic domain of L1CAM.
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PMID:First case of L1CAM gene mutation identified in MASA syndrome in Asia. 1590 36

Loss-of-function mutations of the MECP2 gene at Xq28 are associated with Rett syndrome in females and with syndromic and nonsyndromic forms of mental retardation (MR) in males. By array comparative genomic hybridization (array-CGH), we identified a small duplication at Xq28 in a large family with a severe form of MR associated with progressive spasticity. Screening by real-time quantitation of 17 additional patients with MR who have similar phenotypes revealed three more duplications. The duplications in the four patients vary in size from 0.4 to 0.8 Mb and harbor several genes, which, for each duplication, include the MR-related L1CAM and MECP2 genes. The proximal breakpoints are located within a 250-kb region centromeric of L1CAM, whereas the distal breakpoints are located in a 300-kb interval telomeric of MECP2. The precise size and location of each duplication is different in the four patients. The duplications segregate with the disease in the families, and asymptomatic carrier females show complete skewing of X inactivation. Comparison of the clinical features in these patients and in a previously reported patient enables refinement of the genotype-phenotype correlation and strongly suggests that increased dosage of MECP2 results in the MR phenotype. Our findings demonstrate that, in humans, not only impaired or abolished gene function but also increased MeCP2 dosage causes a distinct phenotype. Moreover, duplication of the MECP2 region occurs frequently in male patients with a severe form of MR, which justifies quantitative screening of MECP2 in this group of patients.
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PMID:Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males. 1608 Jan 19

Mutations in the L1CAM gene cause neurological abnormalities of variable severity, including congenital hydrocephalus, agenesis of the corpus callosum, spastic paraplegia, bilaterally adducted thumbs, aphasia, and mental retardation. Inter- and intrafamilial variability is a well-known feature of the L1CAM spectrum, and several patients have a combination of L1CAM mutations and Hirschsprung's disease (HSCR). We report on two siblings with a missense mutation in exon 7 (p.P240L) of the L1CAM gene. In one of the siblings, congenital dislocation of the radial heads and HSCR were present. Neither patient had hydrocephalus, adducted thumbs, or absent speech, but both had a hypoplastic corpus callosum. We suggest that L1CAM mutation testing should be considered in male patients with a positive family history compatible with X-linked inheritance and either the combination of agenesis of the CC and HSCR or the combination of agenesis of the CC and limb abnormalities, including abnormalities other than adducted thumbs.
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PMID:Expanding the phenotypic spectrum of L1CAM-associated disease. 1665 80

Genetic abnormalities frequently give rise to a mental retardation phenotype. Recent advances in resolution of comparative genomic hybridization and genomic sequence annotation has identified new syndromes at chromosome 3q29 and 9q34. The finding of a significant number of copy number polymorphisms in the genome in the normal population, means that assigning pathogenicity to deletions and duplications in patients with mental retardation can be difficult but has been identified for duplications of MECP2 and L1CAM. Novel autosomal genes that cause mental retardation have been identified recently including CC2D1A identified by homozygosity mapping. Several new genes and pathways have been identified in the field of X-linked mental retardation but many more still await identification. Analysis of families where only a single male is affected reveals that the chance of this being due to a single X-linked gene abnormality is significantly less than would be expected if the excess of males in the population is entirely due to X-linked disease. Recent identification of novel X-linked mental retardation genes has identified components of the post-synaptic density and multiple zinc finger transcription factors as disease causing suggesting new mechanisms of disease causation. The first therapeutic treatments of animal models of mental retardation have been reported, a Drosophila model of Fragile X syndrome has been treated with lithium or metabotropic glutamate receptor (mGluR) antagonists and a mouse model of NF1 has been treated with the HMG-CoA reductase inhibitor lavastatin, which improves the learning and memory skills in these models.
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PMID:The genetics of mental retardation. 1698 73

Mutations in the X-chromosomal gene (L1CAM) for cell adhesion molecule L1 are associated with a heterogeneous group of conditions that include agenesis of the corpus callosum, hydrocephalus, spastic paraplegia, adducted thumbs and mental retardation (L1-spectrum disease, CRASH or MASA syndrome). Although L1CAM is expressed during renal development and L1cam-deficient mice have congenital malformations of the kidney and the urinary tract, L1CAM mutations have not been associated with renal anomalies in men. We report on a boy with prenatally detected hydrocephalus. After his birth, bilateral duplex kidneys and ureters, with a unilateral mega-ureter serving a hydronephrotic upper pole, as well as agenesis of the corpus callosum, adducted thumbs, spasticity, and mental retardation were recognized, fulfilling the criteria of an L1-spectrum disease. Genetic testing of the patient and his mother identified a 2 bp deletion in the invariant splice consensus sequence of intron 18 of L1CAM, predicting a largely truncated or absent protein. At the age of 9 years, 7 years after heminephrectomy, the boy has normal renal function. This observation suggests that patients with L1CAM mutations may have renal abnormalities as seen in the L1cam-deficient mouse model. L1CAM might, therefore, also be considered a possible candidate gene for renal malformations.
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PMID:L1CAM mutation in a boy with hydrocephalus and duplex kidneys. 1729 22

Distal Xq disomy in males results in characteristic phenotypes that typically include mental retardation, microcephaly, prominent hypotonia and hypogonadism. The 8-year-old male patient reported here presented with mental retardation, prominent ears, abnormally wide and unstable gait and flat occiput. He did not have microcephaly or hypogonadism. Subtelomeric multi-fluorescence in-situ hybridization analysis identified a duplicated terminal portion of chromosome Xq/Yq located distally on Yp. Further analysis of the duplicated region using additional FISH probes, specific for the distal Xq and Yp chromosomal regions, and array comparative genomic hybridization analysis using the 244 K oligo-array of Agilent, showed that it spans approximately 2.15 Mb of the terminal Xq region and includes MECP2 but not L1CAM gene. This is the smallest well-characterized terminal Xq duplication reported to date. Genes proximal to MECP2 that are not duplicated in our patient are likely responsible for additional clinical manifestations including characteristic facial dysmorphic features, microcephaly, hypogonadism and more severe hypotonia, as noted in patients with larger distal Xq duplications. Our patient's features are similar to previously reported MECP2 gene duplication cases, thus suggesting minor or no contribution of duplicated genes distal of MECP2 to the reported phenotype.
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PMID:De-novo 2.15 Mb terminal Xq duplication involving MECP2 but not L1CAM gene in a male patient with mental retardation. 1909 26

Research over the last 25 years on the cell adhesion molecule L1 has revealed its pivotal role in nervous system function. Mutations of the human L1CAM gene have been shown to cause neurodevelopmental disorders such as X-linked hydrocephalus, spastic paraplegia and mental retardation. Impaired L1 function has been also implicated in the aetiology of fetal alcohol spectrum disorders, defective enteric nervous system development and malformations of the renal system. Importantly, aberrant expression of L1 has emerged as a critical factor in the development of human carcinomas, where it enhances cell proliferation, motility and chemoresistance. This discovery promoted collaborative work between tumour biologists and neurobiologists, which has led to a substantial expansion of the basic knowledge about L1 function and regulation. Here we provide an overview of the pathological conditions caused by L1 malfunction. We further discuss how the available data on gene regulation, molecular interactions and posttranslational processing of L1 may contribute to a better understanding of associated neurological and cancerous diseases.
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PMID:L1CAM malfunction in the nervous system and human carcinomas. 2023 19

Understanding how cognitive processes including learning, memory, decision making and ideation are encoded by the genome is a key question in biology. Identification of sets of genes underlying human mental disorders is a path towards this objective. Schizophrenia is a common disease with cognitive symptoms, high heritability and complex genetics. We have identified genes involved with schizophrenia by measuring differences in DNA copy number across the entire genome in 91 schizophrenia cases and 92 controls in the Scottish population. Our data reproduce rare and common variants observed in public domain data from >3000 schizophrenia cases, confirming known disease loci as well as identifying novel loci. We found copy number variants in PDE10A (phosphodiesterase 10A), CYFIP1 [cytoplasmic FMR1 (Fragile X mental retardation 1)-interacting protein 1], K(+) channel genes KCNE1 and KCNE2, the Down's syndrome critical region 1 gene RCAN1 (regulator of calcineurin 1), cell-recognition protein CHL1 (cell adhesion molecule with homology with L1CAM), the transcription factor SP4 (specificity protein 4) and histone deacetylase HDAC9, among others (see http://www.genes2cognition.org/SCZ-CNV). Integrating the function of these many genes into a coherent model of schizophrenia and cognition is a major unanswered challenge.
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PMID:Confirmed rare copy number variants implicate novel genes in schizophrenia. 2029

We encountered a family with two boys similarly showing brain atrophy with reduced white matter, hypoplasia of the brain stem and corpus callosum, spastic paralysis, and severe growth and mental retardation without speaking a word. The phenotype of these patients was not compatible with any known type of syndromic leukodystrophy. Presuming an X-linked disorder, we performed next-generation sequencing (NGS) of the transcripts of the entire X chromosome. A single lane of exome NGS in each patient was sufficient. Six potential mutations were found in both affected boys. Two missense mutations, including c.92T>C (p.V31A) in L1CAM, were potentially pathogenic, but this remained inconclusive. The other four could be excluded. Because the patients did not show adducted thumbs or hydrocephalus, the L1CAM change in this family can be interpreted as different scenarios. Personal genome analysis using NGS is certainly powerful, but interpretation of the data can be a substantial challenge requiring a lot of tasks.
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PMID:Exome sequencing of two patients in a family with atypical X-linked leukodystrophy. 2164 43

Any mutations in the human neural cell adhesion molecule L1 (hL1CAM) gene might cause various types of serious neurological syndromes in humans, characterized by increased mortality, mental retardation, and various malformations of the nervous system. Such missense mutations often cause severe abnormalities or even fatalities, and the reason for this may be a disruption of the adhesive function of L1CAM resulting from a misdirection of the degradative pathway. Transfection studies using neuroblastoma N2a cells demonstrated that hL1CAM carrying the missense mutations in the fibronectin-like type III (FnIII) domains most likely is located within the endoplasmic reticulum (ER), but it is less well expressed on the cell surface. One mutant, L935P, in the fourth FnIII domain, was chosen from six mutants (K655 and G698 at Fn1, L935P and P941 at Fn4, W1036 and Y1070 at Fn5) in the FnIII domains to study in detail the functions of hL1CAM(200 kDa) , such as the intracellular traffic and degradation, because only a single band at 200 kDa was detected in the hL1CAM(L935P) -transfected cells. hL1CAM(200 kDa) is expressed predominantly in the ER but not on the cell surface. In addition, this missense mutated hL1CAM(200 kDa) is polyubiquitylated at some sites in the extracellular domain and thus becomes degraded by proteasomes via the ER-associated degradation pathway. These observations demonstrate that the missense mutations of hL1CAM in the FnIII domain may cause the resultant pathogenesis because of a loss of expression on the cell surface resulting from misrouting to the degradative pathway.
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PMID:Human L1CAM carrying the missense mutations of the fibronectin-like type III domains is localized in the endoplasmic reticulum and degraded by polyubiquitylation. 2168 91


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