A nonsense mutation of human XRCC 4 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.

Programmed DNA breaks in lymphoid cells: repair mechanisms and consequences in human disease

“…Similarly, the clinical phenotype presented in these patients was characterized by severe microcephaly, facial dysmorphism and short stature, in the absence of a recognizable immunological phenotype 70. A homozygous mutation resulting in a premature stop codon and very low levels of XRCC4 transcript was found in two patients with progressive neurological defects, confirming the importance of DNA repair and XRCC4 in the brain 71. Another mutation that destabilizes XRCC4 protein, leading to proteasome‐mediated degradation, was also identified recently 72.…”

“…70 A homozygous mutation resulting in a premature stop codon and very low levels of XRCC4 transcript was found in two patients with progressive neurological defects, confirming the importance of DNA repair and XRCC4 in the brain. 71 Another mutation that destabilizes XRCC4 protein, leading to proteasomemediated degradation, was also identified recently. 72 Intriguingly, patient cells are radiosensitive and display a severe DSB repair defect but the patient only manifests with neurological defects without immune deficiency.…”

Cloning, localization and focus formation at DNA damage sites of canine XRCC4

“…It was experimentally observed that absence of XRCC4 results in an impaired ability to repair DSB in rodent cells making it an indispensable factor in NHEJ [7, 21, 22]. Recently, some groups have reported that missense and truncation mutations in XRCC4 cause a human disease including primordial dwarfism [1, 3, 8, 24, 27, 28]. Expectedly, XRCC4-defective patient fibroblasts showed radiosensitivity and diminished DSB repair capacity.…”

Novel XRCC4 Mutations in an Infant With Microcephalic Primordial Dwarfism, Dilated Cardiomyopathy, Subclinical Hypothyroidism, and Early Death: Expanding the Phenotype Of XRCC4 Mutations

“…Bee et al (7) reported monozygotic twin adult males with dilated cardiomyopathy and homozygous XRCC4 mutations (c.673C>T). Their parents were first-degree cousins.…”

“…Thyroid disorders were reported in 2 of the 15 published cases of XRCC4 mutation in the literature; one was a 23-year-old female with XRCC4 compound heterozygous mutations (c. 673C>T, c.760delG) who was reported to have hypothyroidism (5), and multinodular thyroid hypertrophy was described in case 2 of the twin males noted above (7).…”