TBK1 mutation frequencies in French frontotemporal dementia and amyotrophic lateral sclerosis cohorts

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• 作者：Isabelle Le Ber^a ; ^b ; ^c ; ¹ ; Anne De Septenville^a ; ¹ ; Sté ; phanie Millecamps^a ; ¹ ; Agnè ; s Camuzat^a ; Paola Caroppo^a ; ^d ; Philippe Couratier^e ; Fré ; dé ; ric Blanc^f ; Lucette Lacomblez^c ; ^g ; Franç ; ois Sellal^h ; ⁱ ; ^j ; Marie-Cé ; line Fleury^k ; Vincent Meininger^c ; Cé ; cile Cazeneuve^l ; Fabienne Clot^b ; ^l ; Olivier Flabeau^m ; Eric LeGuern^a ; ^l ; Alexis Brice^a ; ^c ; ⁿ ; ^{alexis.brice@upmc.fr" class="auth_mail" title="E-mail the corresponding author} ; the French Clinical ; Genetic Research Network on FTLD/FTLD-ALS²Sophie Auriacombe ; Alexis Brice ; Fré ; dé ; ric Blanc ; Philippe Couratier ; Mira Didic ; Bruno Dubois ; Vé ; ronique Golfier ; Didier Hannequin ; Lucette Lacomblez ; Isabelle Le Ber ; Richard Levy ; Vincent Meininger ; Bernard-Franç ; ois Michel ; Florence Pasquier ; Catherine Thomas-Anterion ; Michè ; le Puel ; Franç ; ois Salachas ; Franç ; ois Sellal ; Martine Vercelletto
• 关键词：TBK1 ; Frontotemporal dementia (FTD) ; Amyotrophic lateral sclerosis (ALS) ; Frontotemporal lobar degeneration (FTLD) ; Optineurin ; Loss of function
• 刊名：Neurobiology of Aging
• 出版年：2015
• 出版时间：November 2015
• 年：2015
• 卷：36
• 期：11
• 页码：3116.e5-3116.e8
• 全文大小：262 K

文摘

TANK1-binding kinase 1 (TBK1) has been recently identified as a new amyotrophic lateral sclerosis (ALS) gene. Loss-of-function (LoF) mutations in TBK1 could be responsible for 0.4%–4% of ALS. Considering the strong genetic overlap existing between frontotemporal dementia (FTD) and ALS, we have evaluated the frequencies of TBK1 mutations in a cohort of French FTD and of ALS patients. We identified 5 LoF mutations, in 4 FTD-ALS and 1 ALS patients. We also identified 5 heterozygous missense variants, predicted to be deleterious, in 1 isolated FTD, 1 FTD-ALS, and 3 ALS cases. Our results demonstrate that TBK1 loss-of-function mutations are more frequent in patients with FTD-ALS (10.8%) than in isolated ALS. TBK1 should thus also be sequenced, after exclusion of C9orf72 mutation, in patients presenting FTD, particularly in cases secondarily associated with ALS.