SSCP ANALYSIS AND SEQUENCING OF THE HUMAN PRION PROTEIN GENE (PRNP) DETECTS 2 DIFFERENT 24-BP DELETIONS IN AN ATYPICAL ALZHEIMERS-DISEASE FAMILY

Alzheimer's disease (AD) is a progressive, degenerative neurological d isorder of the central nervous system. AD is the fourth leading cause of death in elderly persons 65 years or older in Western industrialize d societies. The etiology of AD is unknown, but clinical, pathological , epidemiological, and molecular investigations suggest it is etiologi cally heterogeneous. Mutations in the amyloid protein are rare and seg regate with the disease in a few early-onset familial AD (FAD) familie s. Similarities between AD and the unconventional viral (UCV) diseases , and between the amyloid and prion proteins, implicate the human prio n protein gene (PRNP) as another candidate gene, Single strand conform ation polymorphism (SSCP) analysis was used to screen for mutations at this locus in 82 AD patients from 54 families (30 FAD), vs. 39 age-ma tched controls. A 24-bp deletion around codon 68 that codes for one of five Gly-Pro rich octarepeats was identified in two affected sibs and one offspring of one late-onset FAD family Two other affected sibs, t hree unaffected sibs, and three offspring from this family in addition to one sporadic AD patient and three age-matched controls, were heter ozygous for another octarepeat deletion located around codon 82. Two o f the four affected sibs had features of PD, including one who was aut opsy-verified AD and PD. Although these deletions were found infrequen tly in other AD patients and controls, they appear to be a rare polymo rphism that is segregating in this FAD family. It does not appear that mutations at the PRNP locus are frequently associated with AD in this population. (C) 1995 Wiley Liss, Inc.