Orly Goldstein1, Omri Nayshool1, Beatrice Nefussy1, Bryan J Traynor1, Alan E Renton1, Mali Gana-Weisz1, Vivian E Drory1, Avi Orr-Urtreger2. 1. From The Genetic Institute (O.G., O.N., M.G.-W., A.O.-U.) and the Neuromuscular Service, Department of Neurology (B.N., V.E.D.), Tel Aviv Sourasky Medical Center, Israel; the Laboratory of Neurogenetics (B.J.T., A.E.R.), National Institute on Aging, Bethesda, MD; and the Sackler Faculty of Medicine (V.E.D., A.O.-U.), Tel Aviv University, Israel. 2. From The Genetic Institute (O.G., O.N., M.G.-W., A.O.-U.) and the Neuromuscular Service, Department of Neurology (B.N., V.E.D.), Tel Aviv Sourasky Medical Center, Israel; the Laboratory of Neurogenetics (B.J.T., A.E.R.), National Institute on Aging, Bethesda, MD; and the Sackler Faculty of Medicine (V.E.D., A.O.-U.), Tel Aviv University, Israel. aviorr@tasmc.health.gov.il.
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.
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 OPTN691_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.
Authors: Cyril Pottier; Kevin F Bieniek; NiCole Finch; Maartje van de Vorst; Matt Baker; Ralph Perkersen; Patricia Brown; Thomas Ravenscroft; Marka van Blitterswijk; Alexandra M Nicholson; Michael DeTure; David S Knopman; Keith A Josephs; Joseph E Parisi; Ronald C Petersen; Kevin B Boylan; Bradley F Boeve; Neill R Graff-Radford; Joris A Veltman; Christian Gilissen; Melissa E Murray; Dennis W Dickson; Rosa Rademakers Journal: Acta Neuropathol Date: 2015-05-06 Impact factor: 17.088
Authors: Christopher L Campbell; Pier F Palamara; Maya Dubrovsky; Laura R Botigué; Marc Fellous; Gil Atzmon; Carole Oddoux; Alexander Pearlman; Li Hao; Brenna M Henn; Edward Burns; Carlos D Bustamante; David Comas; Eitan Friedman; Itsik Pe'er; Harry Ostrer Journal: Proc Natl Acad Sci U S A Date: 2012-08-06 Impact factor: 11.205
Authors: David Czell; Peter M Andersen; Christoph Neuwirth; Mitsuya Morita; Markus Weber Journal: Amyotroph Lateral Scler Frontotemporal Degener Date: 2013-01-03 Impact factor: 4.092
Authors: Geraldine A Van der Auwera; Mauricio O Carneiro; Christopher Hartl; Ryan Poplin; Guillermo Del Angel; Ami Levy-Moonshine; Tadeusz Jordan; Khalid Shakir; David Roazen; Joel Thibault; Eric Banks; Kiran V Garimella; David Altshuler; Stacey Gabriel; Mark A DePristo Journal: Curr Protoc Bioinformatics Date: 2013
Authors: Jochen H Weishaupt; Stefan Waibel; Anna Birve; Alexander E Volk; Benjamin Mayer; Thomas Meyer; Albert C Ludolph; Peter M Andersen Journal: Neurobiol Aging Date: 2012-10-10 Impact factor: 4.673
Authors: Jelena Korac; Veronique Schaeffer; Igor Kovacevic; Albrecht M Clement; Benno Jungblut; Christian Behl; Janos Terzic; Ivan Dikic Journal: J Cell Sci Date: 2012-11-23 Impact factor: 5.285
Authors: Chi-Hong Wu; Claudia Fallini; Nicola Ticozzi; Pamela J Keagle; Peter C Sapp; Katarzyna Piotrowska; Patrick Lowe; Max Koppers; Diane McKenna-Yasek; Desiree M Baron; Jason E Kost; Paloma Gonzalez-Perez; Andrew D Fox; Jenni Adams; Franco Taroni; Cinzia Tiloca; Ashley Lyn Leclerc; Shawn C Chafe; Dev Mangroo; Melissa J Moore; Jill A Zitzewitz; Zuo-Shang Xu; Leonard H van den Berg; Jonathan D Glass; Gabriele Siciliano; Elizabeth T Cirulli; David B Goldstein; Francois Salachas; Vincent Meininger; Wilfried Rossoll; Antonia Ratti; Cinzia Gellera; Daryl A Bosco; Gary J Bassell; Vincenzo Silani; Vivian E Drory; Robert H Brown; John E Landers Journal: Nature Date: 2012-08-23 Impact factor: 49.962
Authors: Saurav Guha; Jeffrey A Rosenfeld; Anil K Malhotra; Annette T Lee; Peter K Gregersen; John M Kane; Itsik Pe'er; Ariel Darvasi; Todd Lencz Journal: Genome Biol Date: 2012-01-25 Impact factor: 13.583