title: Novel presenilin 1 variant (P117A) causing Alzheimer's disease in the fourth decade of life.
abstract: Over 160 rare genetic variants in presenilin 1 (PSEN1) are known to cause Alzheimer's disease (AD). In this study we screened a family with early-onset AD for mutations in PSEN1 using direct DNA sequencing. We identified a novel PSEN1 genetic variant which results in the substitution of a Proline with an Alanine at codon 117 (P117A). The P117A variant was present in all demented individuals and fifty percent of at risk individuals. This variant occurs at a site where three other disease-causing variants have been previously observed. In vitro functional studies demonstrate that the P117A variant results in an altered Abeta42/total Abeta ratio consistent with an AD causing mutation. The P117A variant is a novel mutation in PSEN1, which causes early-onset AD in an autosomal dominant manner.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, United States.
authors.forename: John S K
authors.initials: JS
authors.lastname: Kauwe
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Sumi
authors.initials: S
authors.lastname: Chakraverty
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.forename: Andres F
authors.initials: AF
authors.lastname: Henao-Martinez
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000235:genetics* / Q000503:physiopathology; D019943:Amino Acid Substitution / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000235:genetics; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002460:Cell Line; D025063:Chromosome Disorders / Q000235:genetics; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D005799:Genes, Dominant / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008297:Male; D010375:Pedigree; D010446:Peptide Fragments / Q000235:genetics; D017354:Point Mutation / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D053764:Presenilin-1 / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D016229:Amyloid beta-Peptides; D005819:Genetic Markers; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42)