title: Mutations in XRCC4 cause primary microcephaly, short stature and increased genomic instability.
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.
authors.affiliation: Institute of Human Genetics, Center for Molecular Medicine Cologne (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and.
authors.forename: Nadine
authors.initials: N
authors.lastname: Rosin
authors.affiliation: Department of Pediatric Genetics, Marmara University School of Medicine, Istanbul, Turkey.
authors.forename: Nursel H
authors.initials: NH
authors.lastname: Elcioglu
authors.affiliation: Institute of Human Genetics, Center for Molecular Medicine Cologne (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and.
authors.forename: Filippo
authors.initials: F
authors.lastname: Beleggia
authors.affiliation: Department of Pediatric Endocrinology, Sakarya University Medical Faculty, Sakarya, Turkey and.
authors.forename: Pinar
authors.initials: P
authors.lastname: Isgüven
authors.affiliation: Institute of Human Genetics, Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Institute of Medical Genetics, University of Zurich, Zurich-Schlieren, Switzerland.
authors.forename: Katharina
authors.initials: K
authors.lastname: Steindl
authors.affiliation: Institute of Medical Genetics, University of Zurich, Zurich-Schlieren, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Joset
authors.affiliation: Institute of Medical Genetics, University of Zurich, Zurich-Schlieren, Switzerland.
authors.forename: Anita
authors.initials: A
authors.lastname: Rauch
authors.affiliation: Center for Molecular Medicine Cologne (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Institute of Human Genetics, Center for Molecular Medicine Cologne (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and bwollnik@uni-koeln.de.
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
authors.affiliation: Institute of Human Genetics, Center for Molecular Medicine Cologne (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and.
authors.forename: Gökhan
authors.initials: G
authors.lastname: Yigit
mesh_terms: D000293:Adolescent; D001827:Body Height; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D042822:Genomic Instability; D006801:Humans; D007223:Infant; D008297:Male; D008831:Microcephaly / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D017354:Point Mutation; D014421:Turkey
chemical_list: D004268:DNA-Binding Proteins; C101467:XRCC4 protein, human