Human Molecular Genetics Advance Access originally published online on July 15, 2009
Human Molecular Genetics 2009 18(20):3987-3996; doi:10.1093/hmg/ddp323
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Potential late-onset Alzheimer's disease-associated mutations in the ADAM10 gene attenuate 
-secretase activity
1 Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA and 2 TorreyPines Therapeutics, La Jolla, CA 92037, USA
* To whom correspondence should be addressed at: Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Building 114, 16th St. C3009, Charlestown, MA 02129-4404, USA. Tel: +1 6177266845; Fax: +1 6177241949; Email. tanzi{at}helix.mgh.harvard.edu
Received April 30, 2009; Revised July 2, 2009; Accepted July 13, 2009
ADAM10, a member of a disintegrin and metalloprotease family, is an 
-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 -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.