Universität zu Köln

Rosin, Nadine, Elcioglu, Nursel H., Beleggia, Filippo ORCID: 0000-0003-0234-7094, Isguven, Pinar, Altmueller, Janine, Thiele, Holger, Steindl, Katharina, Joset, Pascal, Rauch, Anita ORCID: 0000-0003-2930-3163, Nuernberg, Peter, Wollnik, Bernd and Yigit, Goekhan (2015). Mutations in XRCC4 cause primary microcephaly, short stature and increased genomic instability. Hum. Mol. Genet., 24 (13). S. 3708 - 3718. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Rosin, Nadine UNSPECIFIED UNSPECIFIED UNSPECIFIED Elcioglu, Nursel H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Beleggia, Filippo UNSPECIFIED orcid.org/0000-0003-0234-7094 UNSPECIFIED Isguven, Pinar UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Steindl, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Joset, Pascal UNSPECIFIED UNSPECIFIED UNSPECIFIED Rauch, Anita UNSPECIFIED orcid.org/0000-0003-2930-3163 UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Wollnik, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Yigit, Goekhan UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-400381
DOI:	10.1093/hmg/ddv115
Journal or Publication Title:	Hum. Mol. Genet.
Volume:	24
Number:	13
Page Range:	S. 3708 - 3718
Date:	2015
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2083
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DNA-LIGASE-IV; STRAND BREAK REPAIR; V(D)J RECOMBINATION; MAMMALIAN-CELLS; COMET ASSAY; PROTEIN; COMPLEX; IMPACT; IMMUNODEFICIENCY; IDENTIFICATION Multiple languages Biochemistry & Molecular Biology; Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/40038