CUL4B ubiquitin ligase in mouse development: a model for human X-linked mental retardation syndrome?
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ABSTRACT:
SUBMITTER: Zhao Y
PROVIDER: S-EPMC3411174 | biostudies-other | 2012 Aug
REPOSITORIES: biostudies-other
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Project description:We reevaluated a previously reported family with an X-linked mental retardation syndrome and attempted to identify the underlying genetic defect. Screening of candidate genes in a 10-Mb region on Xq25 implicated CUL4B as the causative gene. CUL4B encodes a scaffold protein that organizes a cullin-RING (really interesting new gene) ubiquitin ligase (E3) complex in ubiquitylation. A base substitution, c.1564C-->T, converted a codon for arginine into a premature termination codon, p.R388X, and rendered the truncated peptide completely devoid of the C-terminal catalytic domain. The nonsense mutation also results in nonsense-mediated mRNA decay in patients. In peripheral leukocytes of obligate carriers, a strong selection against cells expressing the mutant allele results in an extremely skewed X-chromosome inactivation pattern. Our findings point to the functional significance of CUL4B in cognition and in other aspects of human development.
| S-EPMC1821105 | biostudies-literature
Project description:We report a mutation of UBE2A/HR6A, which encodes a ubiquitin-conjugating enzyme (E2), a member of the ubiquitin proteasome pathway, as the cause of a novel X-linked mental retardation (XLMR) syndrome that affects three males in a two-generation family. A single-nucleotide substitution, c.382C-->T in UBE2A, led to a premature UAG stop codon (Q128X). As a consequence, the predicted polypeptide lacks the 25 C-terminal amino acid residues. The importance of this terminal sequence for UBE2 function is inferred by its conservation in vertebrates and in Drosophila. UBE2A mutations do not appear to significantly contribute to XLMR, since no UBE2A mutations were identified in 15 families with nonsyndromic and 4 families with syndromic idiopathic XLMR previously mapped to intervals encompassing this gene. This is the first description of a mutation in a ubiquitin-conjugating enzyme gene as the cause of a human disease.
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Project description:The Lujan-Fryns syndrome or X-linked mental retardation with marfanoid habitus syndrome is a syndromal X-linked form of mental retardation, affecting predominantly males. The prevalence is not known for the general population. The syndrome is associated with mild to moderate mental retardation, distinct facial dysmorphism (long narrow face, maxillary hypoplasia, small mandible and prominent forehead), tall marfanoid stature and long slender extremities, and behavioural problems. The genetic defect is not known. The diagnosis is based on the presence of the clinical manifestations. Genetic counselling is according to X-linked recessive inheritance. Prenatal testing is not possible. There is no specific treatment for this condition. Patients need special education and psychological follow-up, and attention should be given to diagnose early psychiatric disorders.
| S-EPMC1538574 | biostudies-literature
Project description:Rett syndrome (RTT), a common cause of mental retardation in girls, is associated with mutations in the MECP2 gene. Most human cases of MECP2 mutation in girls result in classical or variant forms of RTT. When these same mutations occur in males, they often present as severe neonatal encephalopathy. However, some MECP2 mutations can also lead to diseases characterized as mental retardation syndromes, particularly in boys. One of these mutations, A140V, is a common, recurring missense mutation accounting for about 0.6% of all MeCP2 mutations and ranking 21st by frequency. It has been described in familial X-linked mental retardation (XLMR), PPM- X syndrome (Parkinsonism, Pyramidal signs, Macroorchidism, X-linked mental retardation) and in other neuropsychiatric syndromes. Interestingly, this mutation has been reported to preserve the methyl-CpG binding function of the MeCP2 protein while compromising its ability to bind to the mental retardation associated protein ATRX.We report the construction and initial characterization of a mouse model expressing the A140V MeCP2 mutation. These initial descriptive studies in male hemizygous mice have revealed brain abnormalities seen in both RTT and mental retardation. The abnormalities found include increases in cell packing density in the brain and a significant reduction in the complexity of neuronal dendritic branching. In contrast to some MeCP2 mutation mouse models, the A140V mouse has an apparently normal lifespan and normal weight gain patterns with no obvious seizures, tremors, breathing difficulties or kyphosis.We have identified various neurological abnormalities in this mouse model of Rett syndrome/X-linked mental retardation which may help to elucidate the manner in which MECP2 mutations cause neuronal changes resulting in mental retardation without the confounding effects of seizures, chronic hypoventilation, or other Rett syndrome associated symptoms.
| S-EPMC2836362 | biostudies-literature
Project description:Background and purposeX-linked α-thalassemia/mental retardation syndrome (Mendelian Inheritance in Man, 301040) is one of the X-linked intellectual disability syndromes caused by mutations of the ATRX gene and characterized by male predominance, central hypotonic facies, severe cognitive dysfunction, hemoglobin H disease (α-thalassemia), genital and skeletal abnormalities, and autistic and peculiar behavior. More than 200 patients in the world, including >70 Japanese patients, have been diagnosed with ATR-X syndrome.Materials and methodsWe reviewed the brain MRI and/or CT findings of 27 Japanese patients with ATR-X with ATRX mutations retrospectively.ResultsThe findings were categorized into 5 types: 1) nonspecific brain atrophy (17/27); 2) white matter abnormalities, especially around the trigones (11/27); 3) widespread and scattered white matter abnormalities (1/27); 4) delayed myelination (4/27); and 5) severe and rapidly progressive cortical brain atrophy (1/27).ConclusionsThis is the first report on a comprehensive study of brain MRI/CT findings of ATR-X syndrome. Our findings suggest that the ATRX protein seems to be involved in normal myelination. The classification will require revisions in the near future, but it will be helpful in establishing the relationship between ATRX mutation and brain development and understanding the ATRX protein function in the brain.
| S-EPMC7965407 | biostudies-literature
Project description:Fragile X syndrome (FXS), an inherited disorder characterized by mental retardation and autismlike behaviors, is caused by the failure to transcribe the gene for fragile X mental retardation protein (FMRP), a translational regulator and transporter of select mRNAs. FXS model mice (Fmr1 KO mice) exhibit impaired neuropeptide release. Release of biogenic amines does not differ between wild-type (WT) and Fmr1 KO mice. Rab3A, an mRNA cargo of FMRP involved in the recruitment of vesicles, is decreased by ∼50% in synaptoneurosomes of Fmr1 KO mice; however, the number of dense-core vesicles (DCVs) does not differ between WT and Fmr1 KO mice. Therefore, deficits associated with FXS may reflect this aberrant vesicle release, specifically involving docking and fusion of peptidergic DCVs, and may lead to defective maturation/maintenance of synaptic connections.
| S-EPMC2873207 | biostudies-literature
Project description:We have identified three truncating, two splice-site, and three missense variants at conserved amino acids in the CUL4B gene on Xq24 in 8 of 250 families with X-linked mental retardation (XLMR). During affected subjects' adolescence, a syndrome emerged with delayed puberty, hypogonadism, relative macrocephaly, moderate short stature, central obesity, unprovoked aggressive outbursts, fine intention tremor, pes cavus, and abnormalities of the toes. This syndrome was first described by Cazebas et al., in a family that was included in our study and that carried a CUL4B missense variant. CUL4B is a ubiquitin E3 ligase subunit implicated in the regulation of several biological processes, and CUL4B is the first XLMR gene that encodes an E3 ubiquitin ligase. The relatively high frequency of CUL4B mutations in this series indicates that it is one of the most commonly mutated genes underlying XLMR and suggests that its introduction into clinical diagnostics should be a high priority.
| S-EPMC1785336 | biostudies-literature
Project description:The search for the genetic defects in constitutional diseases has so far been restricted to direct methods for the identification of genetic mutations in the patients' genome. Traditional methods such as karyotyping, FISH, mutation screening, positional cloning and CGH, have been complemented with newer methods including array-CGH and PCR-based approaches (MLPA, qPCR). These methods have revealed a high number of genetic or genomic aberrations that result in an altered expression or reduced functional activity of key proteins. For a significant percentage of patients with congenital disease however, the underlying cause has not been resolved strongly suggesting that yet other mechanisms could play important roles in their etiology. Alterations of the 'native' epigenetic imprint might constitute such a novel mechanism. Epigenetics, heritable changes that do not rely on the nucleotide sequence, has already been shown to play a determining role in embryonic development, X-inactivation, and cell differentiation in mammals. Recent progress in the development of techniques to study these processes on full genome scale has stimulated researchers to investigate the role of epigenetic modifications in cancer as well as in constitutional diseases. We will focus on mental impairment because of the growing evidence for the contribution of epigenetics in memory formation and cognition. Disturbance of the epigenetic profile due to direct alterations at genomic regions, or failure of the epigenetic machinery due to genetic mutations in one of its components, has been demonstrated in cognitive derangements in a number of neurological disorders now. It is therefore tempting to speculate that the cognitive deficit in a significant percentage of patients with unexplained mental retardation results from epigenetic modifications.
| S-EPMC3933076 | biostudies-other
Project description:BackgroundAlpha thalassemia/mental retardation X-linked syndrome (ATR-X) is caused by a mutation at the chromatin regulator gene ATRX. The mechanisms involved in the ATR-X pathology are not completely understood, but may involve epigenetic modifications. ATRX has been linked to the regulation of histone H3 and DNA methylation, while mutations in the ATRX gene may lead to the downstream epigenetic and transcriptional effects. Elucidating the underlying epigenetic mechanisms altered in ATR-X will provide a better understanding about the pathobiology of this disease, as well as provide novel diagnostic biomarkers.ResultsWe performed genome-wide DNA methylation assessment of the peripheral blood samples from 18 patients with ATR-X and compared it to 210 controls. We demonstrated the evidence of a unique and highly specific DNA methylation "epi-signature" in the peripheral blood of ATRX patients, which was corroborated by targeted bisulfite sequencing experiments. Although genomically represented, differentially methylated regions showed evidence of preferential clustering in pericentromeric and telometric chromosomal regions, areas where ATRX has multiple functions related to maintenance of heterochromatin and genomic integrity.ConclusionMost significant methylation changes in the 14 genomic loci provide a unique epigenetic signature for this syndrome that may be used as a highly sensitive and specific diagnostic biomarker to support the diagnosis of ATR-X, particularly in patients with phenotypic complexity and in patients with ATRX gene sequence variants of unknown significance.
| S-EPMC5345252 | biostudies-literature
Project description:Profiling the genomic profiles of mental retardation patients. 13 mental retardation patients were selected for detection of genomic aberrations.
2009-12-16 | GSE19457 | GEO