Potential late-onset Alzheimer's disease-associated mutations in the ADAM10 gene attenuate α-secretase activity

• Published in: Human molecular genetics Vol. 18; no. 20; pp. 3987 - 3996
• Main Authors: Kim, Minji, Suh, Jaehong, Romano, Donna, Truong, Mimy H., Mullin, Kristina, Hooli, Basavaraj, Norton, David, Tesco, Giuseppina, Elliott, Kathy, Wagner, Steven L., Moir, Robert D., Becker, K. David, Tanzi, Rudolph E.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.10.2009
• Subjects: Association Studies; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Medical sciences; Molecular and cellular biology; Neurology; Nervous system diseases; Late; Gene; Alzheimer disease; Central nervous system disease; Genetics; Degenerative disease; Mutation; Cerebral disorder
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddp323

ADAM10, a member of a disintegrin and metalloprotease family, is an α-secretase capable of anti-amyloidogenic proteolysis of the amyloid precursor protein. Here, we present evidence for genetic association of ADAM10 with Alzheimer's disease (AD) as well as two rare potentially disease-associated non-synonymous mutations, Q170H and R181G, in the ADAM10 prodomain. These mutations were found in 11 of 16 affected individuals (average onset age 69.5 years) from seven late-onset AD families. Each mutation was also found in one unaffected subject implying incomplete penetrance. Functionally, both mutations significantly attenuated α-secretase activity of ADAM10 (>70% decrease), and elevated Aβ levels (1.5–3.5-fold) in cell-based studies. In summary, we provide the first evidence of ADAM10 as a candidate AD susceptibility gene, and report two potentially pathogenic mutations with incomplete penetrance for late-onset familial AD.