A novel presenilin 1 mutation (Leu166Arg) associated with early-onset Alzheimer disease.

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Abstract
MUTATIONS IN several genes have been described as causes of Alzheimer disease (AD): the presenilin 1 (PS1) gene in chromosome 14,1 the presenilin 2 gene (PS2) in chromosome 1,2 and the amyloid precursor protein3 in chromosome 21. In addition, several risk factors associated with AD have been described, such as the presence of variants of apolipoprotein E4-7 in chromosome 19, α-antichymotrypsin,8,9 the low-density lipoprotein receptor,10 butyrylcholinesterase K,11 α-2 macroglobulin,12 and a subunit of the α-ketoglutarate dehydrogenase complex.13 The PS1, PS2, and amyloid precursor protein genes have been found to cause familial early-onset AD, whereas the APOE (apolipoprotein E) gene and other risk factors are involved in sporadic or familial AD with different ages at onset. PS1 gene mutations are involved in 18% to 50% of the autosomal dominant early-onset AD cases.1,14-16 More than 40 different mutations of the PS1 gene have been identified in patients with AD in several populations. In addition, a polymorphism in a PS1 intron has been associated with AD being a potential risk factor for late-onset AD.17,18 In contrast, typical PS1 coding mutations result in a dominant inheritance pattern and cause early-onset AD with high penetrance. In the process of screening for mutations in the PS1 gene in patients with familial early-onset AD, we identified a novel mutation in exon 6 (Leu166Arg) in the helical end of transmembrane domain (TM) III, which causes AD in the fourth decade. So far, this domain has not been described as a cluster of mutations in the PS1 gene.