title: A nonsense mutation of human XRCC4 is associated with adult-onset progressive encephalocardiomyopathy.
abstract: We studied two monozygotic twins, born to first cousins, affected by a multisystem disease. At birth, they both presented with bilateral cryptorchidism and malformations. Since early adulthood, they developed a slowly progressive neurological syndrome, with cerebellar and pyramidal signs, cognitive impairment, and depression. Dilating cardiomyopathy is also present in both. By whole-exome sequencing, we found a homozygous nucleotide change in XRCC4 (c.673C>T), predicted to introduce a premature stop codon (p.R225*). XRCC4 transcript levels were profoundly reduced, and the protein was undetectable in patients' skin fibroblasts. XRCC4 plays an important role in non-homologous end joining of DNA double-strand breaks (DSB), a system that is involved in repairing DNA damage from, for example, ionizing radiations. Gamma-irradiated mutant cells demonstrated reduction, but not abolition, of DSB repair. In contrast with embryonic lethality of the Xrcc4 KO mouse, nonsense mutations in human XRCC4 have recently been associated with primordial dwarfism and, in our cases, with adult-onset neurological impairment, suggesting an important role for DNA repair in the brain. Surprisingly, neither immunodeficiency nor predisposition to malignancy was reported in these patients.
authors: Department of Biology, University of Padua, Padua, Italy.
authors: Leonardo
authors: L
authors: Bee
authors: Molecular Neurogenetics Unit, Foundation IRCCS Institute of Neurology "Carlo Besta", Milan, Italy.
authors: Alessia
authors: A
authors: Nasca
authors: Molecular Neurogenetics Unit, Foundation IRCCS Institute of Neurology "Carlo Besta", Milan, Italy.
authors: Alice
authors: A
authors: Zanolini
authors: Department of Biology, University of Padua, Padua, Italy.
authors: Filippo
authors: F
authors: Cendron
authors: Department of Medical Sciences, University of Trieste, Trieste, Italy.
authors: Pio
authors: P
authors: d'Adamo
authors: Department of Biology, University of Padua, Padua, Italy.
authors: Rodolfo
authors: R
authors: Costa
authors: Molecular Neurogenetics Unit, Foundation IRCCS Institute of Neurology "Carlo Besta", Milan, Italy.
authors: Costanza
authors: C
authors: Lamperti
authors: Department of Biology, University of Padua, Padua, Italy.
authors: Lucia
authors: L
authors: Celotti
authors: Molecular Neurogenetics Unit, Foundation IRCCS Institute of Neurology "Carlo Besta", Milan, Italy dghezzi@istituto-besta.it mdz21@mrc-mbu.cam.ac.uk.
authors: Daniele
authors: D
authors: Ghezzi
authors: Molecular Neurogenetics Unit, Foundation IRCCS Institute of Neurology "Carlo Besta", Milan, Italy MRC Mitochondrial Biology Unit, CB2 0XY, Cambridge, UK dghezzi@istituto-besta.it mdz21@mrc-mbu.cam.ac.uk.
authors: Massimo
authors: M
authors: Zeviani
mesh_terms: D000328:Adult; D000818:Animals; D001927:Brain Diseases / Q000150:complications* / Q000235:genetics*; D009202:Cardiomyopathies / Q000150:complications* / Q000235:genetics*; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics*; D005347:Fibroblasts / Q000737:chemistry; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D006720:Homozygote; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D050505:Mutant Proteins / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; D050505:Mutant Proteins; C101467:XRCC4 protein, human
keywords: DNA repair; NHEJ; XRCC4; encephalocardiomyopathy