title: SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis.
abstract: OBJECTIVE
  Mutations in the SQSTM1 gene, coding for p62, are a cause of Paget disease of bone and amyotrophic lateral sclerosis (ALS). Recently, SQSTM1 mutations were confirmed in ALS, and mutations were also identified in 3 patients with frontotemporal dementia (FTD), suggesting a role for SQSTM1 in FTD.
  
  
  OBJECTIVE
  To evaluate the exact contribution of SQSTM1 to FTD and FTD with ALS (FTD-ALS) in an independent cohort of patients.
  
  
  METHODS
  A SQSTM1 mutation was first identified in a multiplex family with FTD by use of whole-exome sequencing. To evaluate the frequency of SQSTM1 mutations, we sequenced this gene in a cohort of patients with FTD or FTD-ALS, with no mutations in known FTD and ALS genes.
  
  
  METHODS
  Primary care or referral center.
  
  
  METHODS
  An overall cohort of 188 French patients, including 132 probands with FTD and 56 probands with FTD-ALS.
  
  
  METHODS
  Frequency of SQSTM1 mutations in patients with FTD or FTD-ALS; description of associated phenotypes.
  
  
  RESULTS
  We identified 4 heterozygous missense mutations in 4 unrelated families with FTD; only 1 family had clinical symptoms of Paget disease of bone, and only 1 family had clinical symptoms of FTD-ALS, possibly owing to the low penetrance of some of the clinical manifestations.
  
  
  CONCLUSIONS
  Although the frequency of the mutations is low in our series (4 of 188 patients [2%]), our results, similar to those already reported, support a direct pathogenic role of p62 in different types of FTD.
authors.affiliation: INSERM, UMR_S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, Hôpital de la Salpêtrière, F-75013, Paris, France2Université Pierre Marie Curie-Paris 06, UMR_S975, F-75013, Paris, France3Centre national de la recherche scientifique, UMR 7225, F-75013, Paris, France4AP-HP, Hôpital de la Pitié-Salpêtrière, Centre de Référence des Démences Rares, Paris, France5AP-HP, Hôpital de la Pitié-Salpêtrière, Département des maladies du système nerveux, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Le Ber
authors.forename: Agnès
authors.initials: A
authors.lastname: Camuzat
authors.forename: Rita
authors.initials: R
authors.lastname: Guerreiro
authors.forename: Kawtar
authors.initials: K
authors.lastname: Bouya-Ahmed
authors.forename: Jose
authors.initials: J
authors.lastname: Bras
authors.forename: Gael
authors.initials: G
authors.lastname: Nicolas
authors.forename: Audrey
authors.initials: A
authors.lastname: Gabelle
authors.forename: Mira
authors.initials: M
authors.lastname: Didic
authors.forename: Anne
authors.initials: A
authors.lastname: De Septenville
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Millecamps
authors.forename: Timothée
authors.initials: T
authors.lastname: Lenglet
authors.forename: Morwena
authors.initials: M
authors.lastname: Latouche
authors.forename: Edor
authors.initials: E
authors.lastname: Kabashi
authors.forename: Dominique
authors.initials: D
authors.lastname: Campion
authors.forename: Didier
authors.initials: D
authors.lastname: Hannequin
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D015331:Cohort Studies; D005192:Family Health; D005260:Female; D005602:France; D057180:Frontotemporal Dementia / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D006147:Guanine / Q000031:analogs & derivatives; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009483:Neuropsychological Tests; D015609:Organotechnetium Compounds; D000071456:Sequestosome-1 Protein; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015609:Organotechnetium Compounds; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C506601:technetium 99m ethylenedicysteine-9-(4-amino-3-(hydroxymethyl)butyl)guanine conjugate; D006147:Guanine
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