title: Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: genetics and neuropathology.
abstract: Mutations in SQSTM1 encoding the sequestosome 1/p62 protein have recently been identified in familial and sporadic cases of amyotrophic lateral sclerosis (ALS). p62 is a component of the ubiquitin inclusions detected in degenerating neurons in ALS patients. We sequenced SQSTM1 in 90 French patients with familial ALS (FALS) and 74 autopsied ALS cases with sporadic ALS (SALS). We identified, at the heterozygote state, one missense c.1175C>T, p.Pro392Leu (exon 8) in one of our FALS and one substitution in intron 7 (the c.1165+1G>A, previously called IVS7+1 G-A, A390X) affecting the exon 7 splicing site in one SALS. These mutations that are located in the ubiquitin-associated domain (UBA domain) of the p62 protein have already been described in Paget's disease and ALS patients carrying these mutations had both concomitant Paget's disease. However, we also identified two novel missense mutations in two SALS: the c.259A>G, p.Met87Val in exon 2 and the c.304A>G, p.Lys102Glu in exon 3. These mutations that were not detected in 360 control subjects are possibly pathogenic. Neuropathology analysis of three patients carrying SQSTM1 variants revealed the presence of large round p62 inclusions in motor neurons, and immunoblot analysis showed an increased p62 and TDP-43 protein levels in the spinal cord. Our results confirm that SQSTM1 gene mutations could be the cause or genetic susceptibility factor of ALS in some patients.
authors: INSERM UMR_S975, CNRS UMR7225, Université Pierre et Marie Curie-Sorbonne Universités, Hôpital Pitié-Salpêtrière, Paris, France.
authors: Elisa
authors: E
authors: Teyssou
authors: Takahiro
authors: T
authors: Takeda
authors: Vincent
authors: V
authors: Lebon
authors: Séverine
authors: S
authors: Boillée
authors: Brahima
authors: B
authors: Doukouré
authors: Guillaume
authors: G
authors: Bataillon
authors: Véronique
authors: V
authors: Sazdovitch
authors: Cécile
authors: C
authors: Cazeneuve
authors: Vincent
authors: V
authors: Meininger
authors: Eric
authors: E
authors: LeGuern
authors: François
authors: F
authors: Salachas
authors: Danielle
authors: D
authors: Seilhean
authors: Stéphanie
authors: S
authors: Millecamps
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin