title: A novel p.Leu(381)Phe mutation in presenilin 1 is associated with very early onset and unusually fast progressing dementia as well as lysosomal inclusions typically seen in Kufs disease.
abstract: Whole exome sequencing in a family with suspected dominant Kufs disease identified a novel Presenilin 1 mutation p.Leu(381)Phe in three brothers who, along with their father, developed progressive dementia and motor deficits in their early 30 s. All affected relatives had unusually rapid disease progression (on average 3.6 years from disease onset to death). In silico analysis of mutation p.Leu(381)Phe predicted more detrimental effects when compared to the common Presenilin 1 mutation p.Glu(280)Ala. Electron microscopy study of peripheral fibroblast cells of the proband showed lysosomal inclusions typical for Kufs disease. However, brain autopsy demonstrated typical changes of Alzheimer's disease.
authors.affiliation: New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Dolzhanskaya
authors.affiliation: Hussman Institute for Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gonzalez
authors.affiliation: Hussman Institute for Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Sperziani
authors.affiliation: Clemson University, Clemson, SC, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Stefl
authors.affiliation: New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Messing
authors.affiliation: New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
authors.forename: Guang Y
authors.initials: GY
authors.lastname: Wen
authors.affiliation: Clemson University, Clemson, SC, USA.
authors.forename: Emil
authors.initials: E
authors.lastname: Alexov
authors.affiliation: Hussman Institute for Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Zuchner
authors.affiliation: New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Milen
authors.initials: M
authors.lastname: Velinov
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D000595:Amino Acid Sequence; D003198:Computer Simulation; D003704:Dementia / Q000235:genetics*; D003937:Diagnosis, Differential; D018450:Disease Progression; D059472:Exome / Q000235:genetics; D017809:Fatal Outcome; D005347:Fibroblasts / Q000648:ultrastructure*; D055106:Genome-Wide Association Study; D006801:Humans; D008247:Lysosomes / Q000648:ultrastructure*; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D009472:Neuronal Ceroid-Lipofuscinoses / Q000473:pathology; D010375:Pedigree; D053764:Presenilin-1 / Q000235:genetics*
chemical_list: D053764:Presenilin-1
keywords: Alzheimer's disease; fast progressing dementia; kufs disease; lysosomal inclusions; presenilin 1 mutation