Elsevier

Neurobiology of Aging

Volume 32, Issue 3, March 2011, Pages 555.e13-555.e14
Neurobiology of Aging

Genetic reports abstract
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Analysis of OPTN as a causative gene for amyotrophic lateral sclerosis

https://doi.org/10.1016/j.neurobiolaging.2010.10.001Get rights and content

Abstract

Mutations in the OPTN gene are well known to be associated with the development of glaucoma. Recently, unique variations in the same gene have been reported in familial and sporadic Japanese cases of amyotrophic lateral sclerosis (ALS). We set out to evaluate the frequency of OPTN mutations in a sample of our familial and sporadic ALS cohorts. All coding exons of the OPTN gene were amplified and sequenced in 95 unrelated familial ALS (FALS) and 95 sporadic ALS (SALS) cases of European descent. Two variants were newly identified in 2 individual FALS cases. Unique variations in the OPTN gene are rare in FALS cases and were not identified in any SALS patients, all of European descent.

Introduction

Amyotrophic lateral sclerosis (ALS) is a severe progressive adult onset neurodegenerative disease characterized by the death of motor neurons located in the motor cortex, brain stem, and ventral horn of the spinal cord. Muscle weakness and spasticity usually progress over a 3- to 5-year period, typically resulting in death from respiratory failure. Three genes are considered to be definitely implicated in a small proportion of classical ALS: SOD1, TARDBP, and FUS (Dion et al., 2009). However, overall, no genetic causative variations have been found for the majority of patients affected with ALS. On the other hand, mutations in the OPTN gene are known to predispose to glaucoma (Rezaie, 2002). Surprisingly, a recent study of Japanese ALS patients identified 2 different variations in the OPTN gene in 2 recessively inherited familial ALS (FALS) cases as well as in 1 sporadic ALS (SALS) patient (Maruyama et al., 2010). They also identified 1 mutation transmitted in an autosomal dominant way with incomplete penetrance in 2 individual FALS patients. In order to confirm those findings in our familial and sporadic ALS cohorts, we sequenced the entire open reading frame of the OPTN gene in 95 FALS and 95 SALS patients of European descent.

Section snippets

Results and discussion

Materials and methods are available as supplementary data. Three variants were found in the same 3 exons in which variants were previously identified in ALS cases. First, the p.K59N missense was identified in 1 FALS patient, but was also found in 1 control participant out of 190 controls tested. Second, a substitution from a guanine to an adenine was identified in the donor splice site located in intron 12 of 1 FALS case. The substitution was followed by the insertion of another adenine (c.

Disclosure statement

Prof. Camu received compensation as a consultant for Merck Serono and Sanofi Aventis, as well as for lectures from Merck Serono. All other authors declare no actual or potential conflict of interest.

Protocols were approved by the ethics committee on human experimentation of the Centre Hospitalier de l'Université de Montréal. All patients gave written informed consent after which patient information and blood were collected.

Acknowledgements

VVB, HD and GAR are supported by the Canadian Institutes of Health Research.

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    Subsequently, more than 40 different OPTN mutations have been identified in both familial and sporadic ALS cases around the world (Table 1 and Fig. 1). However, OPTN mutation frequencies vary greatly among populations, with much higher prevalence in Asian cohorts, especially in Japanese (approximately 4% in familial amyotrophic lateral sclerosis [FALS], 0.23%–1.3% in SALS) (Iida et al., 2012a,b; Ito et al., 2011; Kamada et al., 2014; Li et al., 2015; Maruyama et al., 2010; Naruse et al., 2012; Soong et al., 2014) than in Caucasian patients (up to 1% in FALS) (Beeldman et al., 2015; Belzil et al., 2011; Bury et al., 2016; Chio et al., 2012; Del Bo et al., 2011; Fifita et al., 2017; Goldstein et al., 2016; Johnson et al., 2012; Kenna et al., 2013; Millecamps et al., 2011; Morgan et al., 2015; Ozoguz et al., 2015; Serena et al., 2012; Solski et al., 2012; Sugihara et al., 2011; Tumer et al., 2012; van Blitterswijk et al., 2012; Weishaupt et al., 2013). So far, the genetic epidemiology, clinical characteristics, as well as pathogenicity of OPTN mutations still remain unclear.

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