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Mario Ezquerra, BS; Cristobal Carnero, MD, PhD; Rafael Blesa, MD, PhD; Rafael Oliva, MD, PhD

Arch Neurol. 2000;57:485-488.

Background  Pathogenic mutations in the presenilin 1 (PS1) gene leading to early-onset Alzheimer disease have been described in various populations. The different mutations are not distributed randomly in the PS1 protein but are clustered in some PS1 exons.

Objective  To screen the PS1 gene in search of a potential mutation in a Spanish family with early-onset Alzheimer disease.

Methods  Single-stranded conformational polymorphism and heteroduplex analyses of all exons were used to search for a potential mutation. Subsequent sequencing of the DNA samples with an abnormal heteroduplex pattern was performed to identify the mutation in the sense strand and in the complementary strand.

Results  We found a novel mutation in exon 6 of the PS1 gene at a site that, so far, had not been described as a cluster of mutations. The mutation (an A to C change) causes a substitution of leucine for arginine at position 166 of the PS1 protein and is located adjacent to the transmembrane domain III, where few mutations have been found. In this family, the disease follows an autosomal inheritance pattern with early onset (range, 32-44 years).

Conclusion  A novel missense mutation (Leu166Arg) at an atypical site associated with early-onset Alzheimer disease has been identified in a Spanish family.

From the Genetics Service IDIBAPS—Institut de investigació Biomédica Agustí Pi y Sunyer, Hospital Clínic i Provincial and University of Barcelona (Mr Ezquerra and Dr Oliva) and the Neurology Service, Hospital Clínic i Provincial (Dr Blesa), Barcelona, Spain; and the Neurology Service, Hospital Universitario Virgen de las Nieves, Granada, Spain (Dr Carnero).

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