RT Journal Article
SR Electronic
T1 <em>SOD1</em>, <em>ANG</em>, <em>VAPB</em>, <em>TARDBP</em>, and <em>FUS</em> mutations in familial amyotrophic lateral sclerosis: genotype–phenotype correlations
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 554
OP 560
DO 10.1136/jmg.2010.077180
VO 47
IS 8
A1 Millecamps, Stéphanie
A1 Salachas, François
A1 Cazeneuve, Cécile
A1 Gordon, Paul
A1 Bricka, Bernard
A1 Camuzat, Agnès
A1 Guillot-Noël, Léna
A1 Russaouen, Odile
A1 Bruneteau, Gaëlle
A1 Pradat, Pierre-François
A1 Le Forestier, Nadine
A1 Vandenberghe, Nadia
A1 Danel-Brunaud, Véronique
A1 Guy, Nathalie
A1 Thauvin-Robinet, Christel
A1 Lacomblez, Lucette
A1 Couratier, Philippe
A1 Hannequin, Didier
A1 Seilhean, Danielle
A1 Le Ber, Isabelle
A1 Corcia, Philippe
A1 Camu, William
A1 Brice, Alexis
A1 Rouleau, Guy
A1 LeGuern, Eric
A1 Meininger, Vincent
YR 2010
UL http://jmg.bmj.com/content/47/8/554.abstract
AB Background Mutations in SOD1, ANG, VAPB, TARDBP and FUS genes have been identified in amyotrophic lateral sclerosis (ALS).Methods The relative contributions of the different mutations to ALS were estimated by systematically screening a cohort of 162 families enrolled in France and 500 controls (1000 chromosomes) using molecular analysis techniques and performing phenotype–genotype correlations.Results 31 pathogenic missense mutations were found in 36 patients (20 SOD1, 1 ANG, 1 VAPB, 7 TARDBP and 7 FUS). Surprisingly two FUS mutation carriers also harboured ANG variants. One family of Japanese origin with the P56S VAPB mutation was identified. Seven novel mutations (three in SOD1, two in TARDBP, two in FUS) were found. None of them was detected in controls. Segregation of detected mutations with the disease was confirmed in 11 families including five pedigrees carrying the novel mutations. Clinical comparison of SOD1, TARDBP, FUS and other familial ALS patients (with no mutation in the screened genes) revealed differences in site of onset (predominantly lower limbs for SOD1 and upper limbs for TARDBP mutations), age of onset (younger with FUS mutations), and in lifespan (shorter for FUS carriers). One third of SOD1 patients survived more than 7 years: these patients had earlier disease onset than those presenting with a more typical course. Differences were also observed among FUS mutations, with the R521H FUS mutation being associated with longer disease duration.Conclusions This study identifies new genetic associations with ALS and provides phenotype–genotype correlations with both previously reported and novel mutations.