Familial Alzheimer's disease co-segregates with a Met146I1e substitution in presenilin-1.

The presenilin-1 (PS-1)/S 182 gene at chromosome 14q24.3 is, when mutated, the most common disease gene in autosomal dominant early-onset Alzheimer's disease. Substitution of methionine 146 of the gene product for either valine or leucine co-segregates with Alzheimer's disease with the age of onset in the late thirties or early forties. Here we describe a new substitution of methionine 146 for isoleucine that co-segregates with Alzheimer's disease with age of the onset in the early forties. All identified missense mutations in methionine codon 146 replace one hydrophobic amino acid (Met) with another (Val, Leu, Ile) and correspond to any nucleotide change at the first or third position of the codon. Second position mutations invariably lead to replacement of the hydrophobic methionine with a hydrophilic amino acid that may severely affect the function of the protein. The fact that no second position mutations have been identified so far may support the hypothesis that the protein product of PS-1 plays a crucial role during development.