OPTN 691_692insAG is a founder mutation causing recessive ALS and increased risk in heterozygotes
Citation Manager Formats
Make Comment
See Comments

This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.
Abstract
Objective: To detect genetic variants underlying familial and sporadic amyotrophic lateral sclerosis (ALS).
Methods: We analyzed 2 founder Jewish populations of Moroccan and Ashkenazi origins and ethnic matched controls. Exome sequencing of 2 sisters with ALS from Morocco was followed by genotyping the identified causative null mutation in 379 unrelated patients with ALS and 1,000 controls. The shared risk haplotype was characterized using whole-genome single nucleotide polymorphism array.
Results: We identified 5 unrelated patients with ALS homozygous for the null 691_692insAG mutation in the optineurin gene (OPTN), accounting for 5.8% of ALS of Moroccan origin and 0.3% of Ashkenazi. We also identified a high frequency of heterozygous carriers among patients with ALS, 8.7% and 2.9%, respectively, compared to 0.75% and 1.0% in controls. The risk of carriers for ALS was significantly increased, with odds ratio of 13.46 and 2.97 in Moroccan and Ashkenazi Jews, respectively. We determined that 691_692insAG is a founder mutation in the tested populations with a minimal risk haplotype of 58.5 Kb, encompassing the entire OPTN gene.
Conclusions: Our data show that OPTN 691_692insAG mutation is a founder mutation in Moroccan and Ashkenazi Jews. This mutation causes autosomal recessive ALS and significantly increases the risk to develop the disease in heterozygous carriers, suggesting both a recessive mode of inheritance and a dominant with incomplete penetrance. These data emphasize the important role of OPTN in ALS pathogenesis, and demonstrate the complex genetics of ALS, as the same mutation leads to different phenotypes and appears in 2 patterns of inheritance.
GLOSSARY
- AAO=
- age at onset;
- AJ=
- Ashkenazi Jewish;
- ALS=
- amyotrophic lateral sclerosis;
- AR=
- autosomal recessive;
- CI=
- confidence interval;
- fALS=
- familial amyotrophic lateral sclerosis;
- FTD=
- frontotemporal dementia;
- IBD=
- identical by descent;
- MJ=
- Moroccan Jewish;
- OR=
- odds ratio;
- PCA=
- principal component analysis;
- sALS=
- sporadic amyotrophic lateral sclerosis;
- SNP=
- single nucleotide polymorphism
Footnotes
↵* These authors contributed equally to this work.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Supplemental data at Neurology.org
- Received July 6, 2015.
- Accepted in final form October 9, 2015.
- © 2016 American Academy of Neurology
AAN Members
We have changed the login procedure to improve access between AAN.com and the Neurology journals. If you are experiencing issues, please log out of AAN.com and clear history and cookies. (For instructions by browser, please click the instruction pages below). After clearing, choose preferred Journal and select login for AAN Members. You will be redirected to a login page where you can log in with your AAN ID number and password. When you are returned to the Journal, your name should appear at the top right of the page.
AAN Non-Member Subscribers
Purchase access
For assistance, please contact:
AAN Members (800) 879-1960 or (612) 928-6000 (International)
Non-AAN Member subscribers (800) 638-3030 or (301) 223-2300 option 3, select 1 (international)
Sign Up
Information on how to subscribe to Neurology and Neurology: Clinical Practice can be found here
Purchase
Individual access to articles is available through the Add to Cart option on the article page. Access for 1 day (from the computer you are currently using) is US$ 39.00. Pay-per-view content is for the use of the payee only, and content may not be further distributed by print or electronic means. The payee may view, download, and/or print the article for his/her personal, scholarly, research, and educational use. Distributing copies (electronic or otherwise) of the article is not allowed.
Letters: Rapid online correspondence
REQUIREMENTS
You must ensure that your Disclosures have been updated within the previous six months. Please go to our Submission Site to add or update your Disclosure information.
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
You May Also be Interested in
Dr. David E. Vaillancourt and Dr. Shannon Y. Chiu
► Watch
Topics Discussed
Alert Me
Recommended articles
-
Article
Multiparametric MRI study of ALS stratified for the C9orf72 genotypePeter Bede, Arun L.W. Bokde, Susan Byrne et al.Neurology, June 14, 2013 -
Articles
Hexanucleotide repeat expansions in C9ORF72 in the spectrum of motor neuron diseasesWouter van Rheenen, Marka van Blitterswijk, Mark H.B. Huisman et al.Neurology, July 25, 2012 -
Article
Comparative analysis of C9orf72 and sporadic disease in an ALS clinic populationMfon E. Umoh, Christina Fournier, Yingjie Li et al.Neurology, August 03, 2016 -
Article
Spinocerebellar ataxia type 36 in the Han ChineseYi-Chung Lee, Pei-Chien Tsai, Yuh-Cherng Guo et al.Neurology Genetics, April 12, 2016