Mutations in UBQLN2 are rare in French amyotrophic lateral sclerosis

Abstract

Mutations in UBQLN2 encoding ubiquilin-2 have recently been identified in families with dominant X-linked juvenile and adult-onset amyotrophic lateral sclerosis (ALS) and ALS/dementia. Ubiquilin-2 is a component of the ubiquitin inclusions detected in degenerating neurons in ALS patients. All the previously reported UBQLN2 mutations were localized in 1 of the 12 PXX domains of ubiquilin-2 protein. We sequenced UBQLN2 in 130 French patients with familial ALS (FALS) and absence of male-to-male transmission and the PXX domain in 240 more patients with sporadic ALS (SALS). We identified, at the heterozygote state, the c.1500_1508delCATAGGCCC, p.Gly502_Ile504del, in 1 affected woman. This deletion presumably leads to the in-frame deletion of 1 PXX repeat in the protein. This variant did not segregate with the disease in the corresponding family and was also detected in 1/380 control subject. Our results suggest that UBQLN2 gene mutations are rare in French ALS.

Introduction

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. Skein-like inclusions, which are positive for ubiquitin and TAR DNA-binding protein 43 (TDP-43), are, together with cystatin C-positive Bunina bodies, pathological hallmarks detected in spinal motor neurons of most ALS patients. Recently, 5 different mutations in UBQLN2 gene encoding ubiquilin-2, a member of ubiquitin-like protein family, have been identified in dominant X-linked juvenile ALS, adult-onset ALS, and ALS/dementia (Deng et al., 2011). Evidence supporting the causing role of ubiquilin-2 in ALS were (1) the segregation of the UBQLN2 mutation with ALS disease that has been proven in 4 families; (2) all the previously reported missense mutations affected a proline residue in the evolutionary conserved PXX repeat region; (3) the mutant ubiquilin-2 protein impaired proteasomal protein degradation in vitro; and (4) ubiquilin-2 was shown to be a common component of the skein-like inclusions in sporadic and familial ALS cases (Deng et al., 2011). Although mutant ubiquilin 2 could cause ALS disease through possible gain of toxic function, subsequent genetic analyses of UBQLN2 in different cohorts are needed (Daoud and Rouleau, 2011) and we aimed to confirm the contribution of this gene to ALS in our population of French ALS patients.