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Mutations in XRCC4 cause primary microcephaly, short stature and increased genomic instability

生物 DNA修复蛋白XRCC4 遗传学 基因组不稳定性 非同源性末端接合 突变 小头畸形 DNA修复 身材矮小 癌症研究 基因 DNA错配修复 DNA损伤 DNA 内分泌学
作者
Nicole L. Rosin,Nursel Elçioğlu,Filippo Beleggia,Pınar İşgüven,Janine Altmüller,Hölger Thiele,Katharina Steindl,Pascal Joset,Anita Rauch,Peter Nürnberg,Bernd Wollnik,Gökhan Yiğit
出处
期刊:Human Molecular Genetics [Oxford University Press]
被引量:40
标识
DOI:10.1093/hmg/ddv115
摘要

DNA double-strand breaks (DSBs) are highly toxic lesions, which, if not properly repaired, can give rise to genomic instability. Non-homologous end-joining (NHEJ), a well-orchestrated, multistep process involving numerous proteins essential for cell viability, represents one major pathway to repair DSBs in mammalian cells, and mutations in different NHEJ components have been described in microcephalic syndromes associated, e.g. with short stature, facial dysmorphism and immune dysfunction. By using whole-exome sequencing, we now identified in three affected brothers of a consanguineous Turkish family a homozygous mutation, c.482G>A, in the XRCC4 gene encoding a crucial component of the NHEJ pathway. Moreover, we found one additional patient of Swiss origin carrying the compound heterozygous mutations c.25delG (p.His9Thrfs*8) and c.823C>T (p.Arg275*) in XRCC4. The clinical phenotype presented in these patients was characterized by severe microcephaly, facial dysmorphism and short stature, but they did not show a recognizable immunological phenotype. We showed that the XRCC4 c.482G>A mutation, which affects the last nucleotide of exon 4, induces defective splicing of XRCC4 pre-mRNA mainly resulting in premature protein truncation and most likely loss of XRCC4 function. Moreover, we observed on cellular level that XRCC4 deficiency leads to hypersensitivity to DSB-inducing agents and defective DSB repair, which results in increased cell death after exposure to genotoxic agents. Taken together, our data provide evidence that autosomal recessive mutations in XRCC4 induce increased genomic instability and cause a NHEJ-related syndrome defined by facial dysmorphism, primary microcephaly and short stature.
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