title: High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease.
abstract: Performing exome sequencing in 14 autosomal dominant early-onset Alzheimer disease (ADEOAD) index cases without mutation on known genes (amyloid precursor protein (APP), presenilin1 (PSEN1) and presenilin2 (PSEN2)), we found that in five patients, the SORL1 gene harbored unknown nonsense (n=1) or missense (n=4) mutations. These mutations were not retrieved in 1500 controls of same ethnic origin. In a replication sample, including 15 ADEOAD cases, 2 unknown non-synonymous mutations (1 missense, 1 nonsense) were retrieved, thus yielding to a total of 7/29 unknown mutations in the combined sample. Using in silico predictions, we conclude that these seven private mutations are likely to have a pathogenic effect. SORL1 encodes the Sortilin-related receptor LR11/SorLA, a protein involved in the control of amyloid beta peptide production. Our results suggest that besides the involvement of the APP and PSEN genes, further genetic heterogeneity, involving another gene of the same pathway is present in ADEOAD.
authors.affiliation: Department of Molecular Genetics, Inserm U614, Institute for Biomedical Research and Innovation, University of Rouen, Rouen, France.
authors.forename: C
authors.initials: C
authors.lastname: Pottier
authors.forename: D
authors.initials: D
authors.lastname: Hannequin
authors.forename: S
authors.initials: S
authors.lastname: Coutant
authors.forename: A
authors.initials: A
authors.lastname: Rovelet-Lecrux
authors.forename: D
authors.initials: D
authors.lastname: Wallon
authors.forename: S
authors.initials: S
authors.lastname: Rousseau
authors.forename: S
authors.initials: S
authors.lastname: Legallic
authors.forename: C
authors.initials: C
authors.lastname: Paquet
authors.forename: S
authors.initials: S
authors.lastname: Bombois
authors.forename: J
authors.initials: J
authors.lastname: Pariente
authors.forename: C
authors.initials: C
authors.lastname: Thomas-Anterion
authors.forename: A
authors.initials: A
authors.lastname: Michon
authors.forename: B
authors.initials: B
authors.lastname: Croisile
authors.forename: F
authors.initials: F
authors.lastname: Etcharry-Bouyx
authors.forename: C
authors.initials: C
authors.lastname: Berr
authors.forename: J-F
authors.initials: JF
authors.lastname: Dartigues
authors.forename: P
authors.initials: P
authors.lastname: Amouyel
authors.forename: H
authors.initials: H
authors.lastname: Dauchel
authors.forename: C
authors.initials: C
authors.lastname: Boutoleau-Bretonnière
authors.forename: C
authors.initials: C
authors.lastname: Thauvin
authors.forename: T
authors.initials: T
authors.lastname: Frebourg
authors.forename: J-C
authors.initials: JC
authors.lastname: Lambert
authors.forename: D
authors.initials: D
authors.lastname: Campion
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D016022:Case-Control Studies; D018389:Codon, Nonsense / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics / Q000523:psychology; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; C102582:SORL1 protein, human