title: A novel PSEN1 gene mutation (L235R) associated with familial early-onset Alzheimer's disease.
abstract: Mutations in the presenilin 1 (PSEN1) gene are the most frequent cause of familial Alzheimer's disease (AD), with at least 182 different mutations published to date. We report a 48-year-old woman (age at onset 47 years) who presented a progressive alteration of episodic memory, spatial disorientation, apathy, language disturbances and neglect of personal care. Her MMSE score was 20/30. The patient presented an unusually rapid deterioration and at 6 months follow-up her cognitive and functional status had worsened considerably (MMSE score of 11). Cranial MRI showed a bilateral atrophy with temporal and parietal predominance and the quantification of AD CSF biomarkers showed the typical AD signature. Family history evidenced an autosomal dominant pattern of inheritance. Mutational screening was performed by direct sequencing of exons 3-12 of PSEN1. The patient presented the 3/3 APOE genotype. Genetic analysis revealed a nucleotide substitution in exon 7 of PSEN1 gene, producing a missense mutation in codon 235 from leucine amino acid to arginine (L235R). This amino acid is conserved between presenilin-1 and presenilin-2 proteins. The L235R mutation had not been previously reported, although other mutations in the same residue have also been associated with familial early-onset AD, providing support for the importance of this residue for the presenilin-1 function.
authors.affiliation: Genetic Counselling Program for Familial Dementia, Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clínic, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), C/Villarroel, 170, 08036 Barcelona, Spain. antonell@clinic.ub.es
authors.forename: Anna
authors.initials: A
authors.lastname: Antonell
authors.forename: Mircea
authors.initials: M
authors.lastname: Balasa
authors.forename: Rafael
authors.initials: R
authors.lastname: Oliva
authors.forename: Albert
authors.initials: A
authors.lastname: Lladó
authors.forename: Beatriz
authors.initials: B
authors.lastname: Bosch
authors.forename: Neus
authors.initials: N
authors.lastname: Fabregat
authors.forename: Juan
authors.initials: J
authors.lastname: Fortea
authors.forename: José Luis
authors.initials: JL
authors.lastname: Molinuevo
authors.forename: Raquel
authors.initials: R
authors.lastname: Sánchez-Valle
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D001120:Arginine / Q000235:genetics*; D005192:Family Health; D005260:Female; D006801:Humans; D021621:Imaging, Three-Dimensional / Q000379:methods; D007930:Leucine / Q000235:genetics*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010296:Parietal Lobe / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics*; D013702:Temporal Lobe / Q000473:pathology
chemical_list: C508853:PSEN1 protein, human; D053764:Presenilin-1; D001120:Arginine; D007930:Leucine