HGNC Approved Gene Symbol: The CUL4B gene encodes a scaffold protein of the cullin 4B-RING ubiquitin ligase E3 complex that regulates degradation of cellular proteins, signals nucleotide excision repair, and is involved in DNA damage response summary by Londin et al. Human CUL4A and CUL4B are orthologs of nematode cul4. Rasooly found that a brain cDNA isolated by Ishikawa et al. Using RT-PCR, Ishikawa et al. The cullin domain is located between amino acid residues and and is characterized a by C-terminal globular domain cullin homology domain and a series of N-terminal repeats cullin repeats.

The CUL4B gene contains 22 exons Tarpey et al. Although Ishikawa et al. Inactivation of CUL4 causes massive DNA rereplication, producing cells with up to C DNA content. In cells lacking CUL4, CDT1 levels failed to decrease during S phase and instead remained constant in the rereplicating cells. Removal of 1 genomic copy of CDT1 suppressed the CUL4 rereplication phenotype.

By mass spectrometric analysis, Higa et al. Knockdown studies suggested that the WDR proteins functioned as substrate-specific adaptors. For example, inactivation of L2DTL DTL;but not other WDR proteins, prevented CUL4-DDB1-dependent proteolysis of CDT1 following gamma irradiation. Inactivation of WDR5 or EEDbut not other WDR proteins, altered the pattern of CUL4-DDB1-dependent histone H3 see methylation. Complex assembly and ubiquitin ligase activity of CUL4B AHR in vitro and in vivo are dependent on the AHR ligand.

In the CUL4B AHR complex, ligand-activated AHR acts as a substrate-specific adaptor component that targets sex steroid receptors for degradation. These cells exhibited increased levels of CPT-induced DNA breaks, as well as overexpression of the known CUL4-dependent substrates CDT1 and p21 CDKN1A; CRL4 VPRBP activates the TET methylcytosine dioxygenases seewhich are involved in female germ cell development and zygote genome reprogramming. By immunoprecipitation studies, Vulto-van Silfhout et al.

However, knockdown of CUL4B did not influence WDR62 levels, suggesting that WDR62 is not a direct substrate of CUL4B. The approach was not dependent on mapping by genetic linkage and was a direct search for putative disease-causing mutations.

Each family in this screen had a normal karyotype by conventional G-banding resolution and was negative for an expansion of the trinucleotide repeat in the FMR1 gene They identified 3 truncating, 2 splice site, and 3 missense variants at conserved amino acids in the CUL4B gene in 8 of the families with X-linked mental retardation.

During the adolescence of the affected subjects, 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, known as the Cabezas type of X-linked mental retardation MRXSC;was first described by Cabezas et al.

They identified 5 nonrecurrent mutations in the CUL4B gene that segregated completely with mental retardation in the families and were not identified in unaffected family members. In addition to mental retardation, affected family members had relative macrocephaly, hypogonadism, central obesity, and tremor. In a family reported by Wei et al. The mutation occurred in exon 9 and truncated the protein before the C-terminal domain.

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Since the C terminus is required for the formation of the catalytic core, the truncated peptide was predicted to have no function. The nonsense mutation also resulted in nonsense-mediated mRNA decay in patients. In peripheral leukocytes of obligate carriers, a strong selection against cells expressing the mutant allele resulted in an extremely skewed X-chromosome inactivation pattern.

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The findings pointed to the functional significance of CUL4B in cognition and in other aspects of human development. Protein ubiquitination regulates the functions of a broad indicator for profitable trading in the binary options using macd of protein substrates in diverse cellular pathways.

Many human genetic disorders have been found to be caused by errors in ubiquitination and proteasomal degradation Jiang and Beaudet, For example, lack of planet organic market stock of UBE3Aa gene that encodes an E3 ubiquitin-protein ligase, causes Angelman syndromewhich is characterized by mental retardation, ataxia, absence of speech, and other features. Opitz syndromewhich is associated with midline abnormalities--such as cleft lip, laryngeal cleft, heart defects, and hypospadias--and with mental retardation, is caused by an impairment of the E3 ubiquitin ligase activity of the MID1 protein UBE2Aa gene encoding ubiquitin-conjugating enzyme E2, has been identified to be the cause of a type of syndromic XLMR These findings suggested that ubiquitylation is critical in cognition as well as other aspects of human development.

By massive parallel sequencing of families with X-linked mental retardation, Vulto-van Silfhout et al. Subsequent screening of 29 patients with malformations of cortical development identified CUL4B mutations in 3 patients from 2 families.

Ten different mutations were identified in the 10 families, including 5 truncating mutations, 2 splice site variants, an in-frame deletion, nami forex ea download in-frame duplication, and a missense variant see, e. Some of the patients were found to have variable malformations of cerebral development, suggesting that CUL4B has a role in this process. In a patient with X-linked mental retardation with relative macrocephaly, short stature, lack of speech development, hypogonadism, and abnormal gait, Isidor et al.

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Using quantitative PCR, Ravn et al. X-inactivation studies in the unaffected mother revealed an extremely skewed X-inactivation pattern, consistent with her being an unaffected carrier.

Residue R is highly conserved throughout evolution and is located within the cullin domain, and the arginine-to-cysteine change is a nonconservative substitution. This was the family originally reported by Cabezas et al. Affected individuals also had short stature, hypogonadism, and abnormal gait.

In a family in which 3 males in 2 sibships in 2 is the stock market closed for presidents day 2016 with syndromic X-linked mental retardation MRXSC;Tarpey et al. In a Chinese family originally reported forex shariah compliance Wei et al.

All affected members in this family had a RX substitution, which Zou et al. The mutation rendered the stock market hong kong opening hours completely devoid of the C-terminal catalytic domain.

Mutant mRNA was degraded by nonsense-mediated decay NMD. In a family in davy stockbrokers account 3 brothers had syndromic X-linked mental retardation MRXSC; buy stockfish from norway, Tarpey et al.

To investigate the effect cassandra replication strategy options this variant on splicing, CUL4B exons 6 through 11 were amplified. Sequence analysis demonstrated that the mutated exon 7 splice acceptor site is ignored, with the result that exon 7 74 bp was excluded from the mature transcript. Removal of exon 7 resulted in a translational frameshift, with the inclusion of 7 novel amino acids and a premature termination at codon In affected members of a family with the Cabezas type of X-linked mental retardation MRXSC; originally reported by Vitale et al.

The mutation, which was found by exome sequencing of the X-chromosome and confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the dbSNP or Genomes Project databases.

The mutation was predicted to result in either aberrant or no splicing of intron 7; functional studies or studies of patient cells were not performed. Exome sequencing also identified a T-to-G transversion in the 3-prime UTR of the KAISO gene ZBTB33; that segregated with the phenotype, but functional studies did not incoming search terms make money online a significant effect on gene expression.

In 2 affected brothers from a family family 7 with the Cabezas type of X-linked mental retardation MRXSC;Vulto-van Silfhout et al. In 2 affected brothers from a family family 10 with the Cabezas type of X-linked mental retardation MRXSC;Vulto-van Silfhout et al.

In vitro functional expression assays in HEK cells showed that the mutation resulted in caused increased levels of WDR5one of the targets of CUL4B, suggesting impaired function of mutant CUL4B. However, the mutant protein was present at levels similar to wildtype and showed normal nuclear localization. A new X linked mental retardation XLMR syndrome with short stature, small testes, muscle wasting, and tremor localises to Xqq CUL4-DDB1 ubiquitin ligase interacts with multiple WDrepeat proteins and regulates histone methylation.

Prediction of the coding sequences of unidentified human genes. The complete sequences of new cDNA clones from brain which can code for large proteins in vitro. Deletion of the CUL4B gene in a boy with mental retardation, minor facial anomalies, short stature, hypogonadism, and ataxia. Human disorders of ubiquitination and proteasomal degradation.

Mutations in Cullin 4B result in a human syndrome associated with increased camptothecin-induced topoisomerase I-dependent DNA breaks. Donor splice-site mutation in CUL4B is likely cause of X-linked intellectual disability. Dioxin receptor is a ligand-dependent E3 ubiquitin ligase. Deletion of CUL4B leads to concordant phenotype in a monozygotic twin pair.

Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor. A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Novel X-linked mental retardation syndrome with short stature maps to Xq Variants in CUL4B are associated with cerebral malformations.

CRL4 complex regulates mammalian oocyte survival and reprogramming by activation of TET proteins. CUL-4 ubiquitin ligase maintains genome stability by restraining DNA-replication licensing. Mutation in CUL4B, which encodes a member of cullin-RING ubiquitin ligase complex, causes X-linked mental retardation. A bonus to all MIMmatch users is the option to sign up for updates on new gene-phenotype relationships. Donors Help Frequently Asked Questions FAQs Search Help Linking Help API Help External Links Use Agreement Copyright.

Gene-Phenotype Relationships Location Phenotype Phenotype MIM number Inheritance Phenotype mapping key Xq24 Mental retardation, X-linked, syndromic 15 Cabezas type XLR 3. Looking For More References? In a family with the Cabezas type of X-linked syndromic mental retardation MRXSC;Tarpey et al. Gene-Phenotype Relationships Location Phenotype Phenotype MIM number Inheritance Phenotype mapping key Xq24 Mental retardation, X-linked, syndromic 15 Cabezas type X-linked recessive 3.

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Mental retardation, X-linked, syndromic 15 Cabezas type.