back to Fifth International Conference
Two Homologous Genes Associated with Early Onset Familial
P.H. St. George-Hyslop, E.I. Rogaev, R. Sherrington, E.A.
Rogaev, G. Levesque, M. Ikeda, Y. Liang, H. Chi, C. Lin,
K. Holman, P.E. Fraser, and J.M. Rommens
Centre for Research in Neurodegenerative Diseases, Dept. of Medicine, University
of Toronto, Toronto, Canada M5S 3H2
We have isolated two homologous genes which bear missense mutations in affected
members of pedigrees with autosomal dominant early onset Alzheimer disease.
The first, presenilin 1 (PS1) was cloned from chromosome 14 by positional
cloning of the AD3 trait. This gene is predicted to encode a 467 residue
polypeptide bearing at least 9 hydrophobic domains and two acidic hydrophillic
loops. The second, presenilin 2 (PS2), was isolated on the basis of its
sequence homology to PS1, and bears a similar structure, but differs significantly
from PS1 in the amino acid sequence of the N-terminal and internal acidic
hydrophillic domains. Missense and splicing mutants preserving the reading
(>20 known mutations in PS1 and 2 known mutants in PS2) occur in conserved
residues and are associated with fully penetrant very early onset AD (onset
30-65 yrs) in PS1, and with highly penetrant early onset AD (onset 65-85
years) in PS2. Both genes are widely expressed, but PS2 is expressed at
higher levels in pancreas and cardiac and skeletal muscle. Both genes have
numerous concensus sequences for phosphorylation by PKC and MAP kinase,
but it is currently unknown if these sites are actually phosphorylated.
Preliminary immunocytochemical studies using antibodies raised against the
non-conserved domains of these proteins suggest that both proteins are predominantly
intracellular, located in the ER, Golgi and perinuclear envelope.