Genetic reports abstractMutations in UBQLN2 are rare in French amyotrophic lateral sclerosis
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.
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Methods
The unique coding exon (with 125 base pairs of the 5′ untranslated region and 293 base pairs of the 3′ untranslated region) of UBQLN2 (Ensembl reference sequence: ENSG00000188021) was sequenced in 130 French familial ALS (FALS) patients without male-to-male transmission (69 men and 61 women). The PXX repeat domain was further sequenced in 240 sporadic ALS (SALS) patients (140 men and 100 women). Control samples (n = 380) were obtained from age-matched Caucasian individuals of French background
Results
We identified, at the heterozygote state, the c.1500_1508delCATAGGCCC, p.Gly502_Ile504del, in 1 affected woman (Supplementary Fig. 1B). This ALS patient had a bulbar disease onset at the age of 52 and died at 54 after a disease evolution of 27 months. The disease seemed to be transmitted in a dominant manner in this family with 3 affected patients in 3 generations (Supplementary Fig. 1A). The index case's father started the disease at 64 years with bulbar onset and died after 31 months of
Discussion
Mutations in UBQLN2 were reported to be responsible for approximately 2% of FALS devoid of male-to-male transmission (Deng et al., 2011). Our analysis in 130 FALS identified only 1 in-frame deletion variant in this gene. Despite this variant being localized in the hot spot PXX domain of the protein, it did not seem to be the causing genetic defects in the corresponding family. Indeed it did not segregate with the disease in the family and it was further detected in 1 healthy female control.
Disclosure statement
The authors declare no actual or potential conflicts of interest.
Protocols were approved by the Medical Research Ethics Committee of “Assistance Publique-Hôpitaux de Paris” and all participants signed a consent form for the research.
Acknowledgements
We are grateful to the patients and their families. Marine Giraudeau and Elisa Teyssou are gratefully acknowledged for technical help. We thank the Généthon cell and DNA Bank (Évry, France) and the CRicm DNA and cell bank (Paris, France) for patients' DNA. This work was financed by the Association pour la Recherche sur la Sclérose latérale amyotrophique et autres maladies du motoneurone (ARSla, France) and by Association française contre les myopathies (AFM, France).
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