A novel mutation in the PSEN2 gene (T430M) associated with variable expression in a family with early-onset Alzheimer disease.
BACKGROUND
Autosomal dominant early-onset Alzheimer disease is a heterogeneous condition that has been associated with mutations in 3 different genes: the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes. Most cases are due to mutations in the PSEN1 gene, whereas mutations in the APP and PSEN2 genes are rare.


OBJECTIVE
To describe a novel mutation in the PSEN2 gene associated with early-onset autosomal dominant Alzheimer disease.


METHODS
The proband was a 49-year-old individual who displayed progressive dementia beginning at age 45 years. One of the parents and one of the grandparents had developed dementia at ages 64 years and 60 years, respectively, and 1 sibling had mild cognitive impairment. Some family members also had Tourette syndrome. Mutation analysis of the APP, PSEN1, PSEN2, and tau (TAU) genes was performed. Apolipoprotein E (APOE) was also genotyped.


RESULTS
We found a missense mutation at codon 430 of the PSEN2 gene that predicts a threonine-to-methionine substitution. This mutation was detected in the affected individuals and in 1 cognitively healthy sibling. The mutation was absent in 260 control chromosomes. The normal amino acid was conserved in the human and mouse PSEN1 and mouse PSEN2 homologues. No influence of the APOE genotype was observed.


CONCLUSIONS
We have found a novel mutation in the PSEN2 gene in a family with early-onset Alzheimer disease. The variation in the age at onset confirms that PSEN2 mutations are associated with variable clinical expression.
Ezquerra
Mario
M
Genetics Service, Department of Ciencias Fisiologicas I, University of Barcelona, Institut de Investigacions Biomédiques Agustí Pi i Sunyer, Hospital Clínic, Villaroel 170, 08036 Barcelona, Spain.
Lleó
Alberto
A
Castellví
Magda
M
Queralt
Rosa
R
Santacruz
Pilar
P
Pastor
Pau
P
Molinuevo
José Luis
JL
Blesa
Rafael
R
Oliva
Rafael
R
D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics*; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D004252:DNA Mutational Analysis; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D053766:Presenilin-2; D005879:Tourette Syndrome / Q000150:complications
D008565:Membrane Proteins; C508861:PSEN2 protein, human; D053766:Presenilin-2