Identification of a novel mutation (Leu282Arg) of the human presenilin 1 gene in Alzheimer's disease.

Many different mutations, causative of Alzheimer's disease, have been found in the presenilin-1 gene (PS-1). We have developed a screening method based on denaturing gradient gel electrophoresis (DGGE), which allows the mutational analysis of the whole exon 9 of PS-1. Upon the screening of a Spanish sample of early onset familial Alzheimer disease cases, we have found a novel mutation in the PS-1 gene. The mutation (a T to G transition) results in a change of the amino acid at position 282 of the presenilin protein from leucine to arginine. This mutation is located in the hydrophobic domain number 7 (exon 9) close to the site of physiological cleavage processing. The average of onset of the affected members of this family is 43+/-5 years, and the average age of exitus of affected members is 56+/-3 years. The possibility to determine the specific pathologic mechanisms of this mutation is now open.