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X-ray repair cross complementing 4 OKDB#: 5527
 Symbols: XRCC4 Species: human
 Synonyms: SSMED  Locus: 5q14.2 in Homo sapiens


For retrieval of Nucleotide and Amino Acid sequences please go to: OMIM Entrez Gene
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General Comment NCBI Summary: The protein encoded by this gene functions together with DNA ligase IV and the DNA-dependent protein kinase in the repair of DNA double-strand breaks. This protein plays a role in both non-homologous end joining and the completion of V(D)J recombination. Mutations in this gene can cause short stature, microcephaly, and endocrine dysfunction (SSMED). Alternate transcript variants such as NM_022406 are unlikely to be expressed in some individuals due to a polymorphism (rs1805377) in the last splice acceptor site. [provided by RefSeq, Oct 2019]
General function DNA repair, Enzyme
Comment
Cellular localization Nuclear
Comment
Ovarian function
Comment
Expression regulated by
Comment
Ovarian localization
Comment
Follicle stages
Comment
Phenotypes POF (premature ovarian failure)
Mutations 2 mutations

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: An XRCC4 splice mutation associated with severe short stature, gonadal failure, and early-onset metabolic syndrome. de Bruin C et al. (2015) Severe short stature can be caused by defects in numerous biological processes including defects in IGF-1 signaling, centromere function, cell cycle control, and DNA damage repair. Many syndromic causes of short stature are associated with medical comorbidities including hypogonadism and microcephaly. To identify an underlying genetic etiology in two siblings with severe short stature and gonadal failure. Clinical phenotyping, genetic analysis, complemented by in vitro functional studies of the candidate gene. An academic pediatric endocrinology clinic. Two adult siblings (male patient [P1] and female patient 2 [P2]) presented with a history of severe postnatal growth failure (adult heights: P1, -6.8 SD score; P2, -4 SD score), microcephaly, primary gonadal failure, and early-onset metabolic syndrome in late adolescence. In addition, P2 developed a malignant gastrointestinal stromal tumor at age 28. Single nucleotide polymorphism microarray and exome sequencing. Combined microarray analysis and whole exome sequencing of the two affected siblings and one unaffected sister identified a homozygous variant in XRCC4 as the probable candidate variant. Sanger sequencing and mRNA studies revealed a splice variant resulting in an in-frame deletion of 23 amino acids. Primary fibroblasts (P1) showed a DNA damage repair defect. In this study we have identified a novel pathogenic variant in XRCC4, a gene that plays a critical role in non-homologous end-joining DNA repair. This finding expands the spectrum of DNA damage repair syndromes to include XRCC4 deficiency causing severe postnatal growth failure, microcephaly, gonadal failure, metabolic syndrome, and possibly tumor predisposition.//////////////////

Species: mouse
Mutation name:
type: null mutation
fertility: embryonic lethal
Comment: A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis. Gao Y et al. (1999) XRCC4 was identified via a complementation cloning method that employed an ionizing radiation (IR)-sensitive hamster cell line. By gene-targeted mutation, we show that XRCC4 deficiency in primary murine cells causes growth defects, premature senescence, IR sensitivity, and inability to support V(D)J recombination. In mice, XRCC4 deficiency causes late embryonic lethality accompanied by defective lymphogenesis and defective neurogenesis manifested by extensive apoptotic death of newly generated postmitotic neuronal cells. We find similar neuronal developmental defects in embryos that lack DNA ligase IV, an XRCC4-associated protein. Our findings demonstrate that differentiating lymphocytes and neurons strictly require the XRCC4 and DNA ligase IV end-joining proteins and point to the general stage of neuronal development in which these proteins are necessary.//////////////////

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Phenotypes and GWAS show phenotypes and GWAS
Links
OMIM (Online Mendelian Inheritance in Man: an excellent source of general gene description and genetic information.)
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created: Dec. 31, 2017, 1:33 p.m. by: system   email:
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last update: April 2, 2020, 3:59 p.m. by: hsueh    email:



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