A novel PSEN1 gene mutation (L235R) associated with familial early-onset Alzheimer's disease

• Published in: Neuroscience letters 2011-05, Vol.496 (1), p.40-42
• Main Authors: Antonell, Anna, Balasa, Mircea, Oliva, Rafael, Lladó, Albert, Bosch, Beatriz, Fabregat, Neus, Fortea, Juan, Molinuevo, José Luis, Sánchez-Valle, Raquel
• Format: Article
• Language: English
• Subjects: Adult; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer's disease (AD); Arginine - genetics; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Early-onset; Family Health; Female; Fundamental and applied biological sciences. Psychology; Humans; Imaging, Three-Dimensional - methods; Leucine - genetics; Magnetic Resonance Imaging - methods; Medical sciences; Middle Aged; Mutation; Mutation - genetics; Neurology; Parietal Lobe - pathology; Presenilin 1; Presenilin-1 - genetics; Rapid progression; Temporal Lobe - pathology; Vertebrates: nervous system and sense organs
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2011.03.084

► A novel missense mutation in the PSEN1 gene which cause a change of aminoacid (L235R). ► The mutation is probably pathogenic and associated with autosomal dominant early-onset AD. ► This mutation had not been previously reported and is associated with a rapid clinical progression. 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.