CLONING OF A GENE BEARING MISSENSE MUTATIONS IN EARLY-ONSET FAMILIAL ALZHEIMERS-DISEASE

Some cases of Alzheimer's disease are inherited as an autosomal domina nt trait. Genetic linkage studies have mapped a locus (AD3) associated with susceptibility to a very aggressive form of Alzheimer's disease to chromosome 14q24.3. We have defined a minimal cosegregating region containing the AD3 gene, and isolated at least 19 different transcript s encoded within this region. One of these transcripts (S182) correspo nds to a novel gene whose product is predicted to contain multiple tra nsmembrane domains and resembles an integral membrane protein. Five di fferent missense mutations have been found that cosegregate with early -onset familial Alzheimer's disease. Because these changes occurred In conserved domains of this gene, and are not present in normal control s, they are likely to be causative of AD3.