title: Potential late-onset Alzheimer's disease-associated mutations in the ADAM10 gene attenuate {alpha}-secretase activity.
abstract: ADAM10, a member of a disintegrin and metalloprotease family, is an alpha-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 alpha-secretase activity of ADAM10 (>70% decrease), and elevated Abeta 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.
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Minji
authors.initials: M
authors.lastname: Kim
authors.forename: Jaehong
authors.initials: J
authors.lastname: Suh
authors.forename: Donna
authors.initials: D
authors.lastname: Romano
authors.forename: Mimy H
authors.initials: MH
authors.lastname: Truong
authors.forename: Kristina
authors.initials: K
authors.lastname: Mullin
authors.forename: Basavaraj
authors.initials: B
authors.lastname: Hooli
authors.forename: David
authors.initials: D
authors.lastname: Norton
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Tesco
authors.forename: Kathy
authors.initials: K
authors.lastname: Elliott
authors.forename: Steven L
authors.initials: SL
authors.lastname: Wagner
authors.forename: Robert D
authors.initials: RD
authors.lastname: Moir
authors.forename: K David
authors.initials: KD
authors.lastname: Becker
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism*; D000072197:ADAM10 Protein; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide
chemical_list: D008565:Membrane Proteins; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human