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http://purl.uniprot.org/citations/27066578http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/27066578http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/27066578http://www.w3.org/2000/01/rdf-schema#comment"

Objective

The genetic risk architecture of Alzheimer disease (AD) is complex with single pathogenic mutations leading to early-onset AD, while both rare and common genetic susceptibility variants contribute to the more widespread late-onset AD (LOAD); we sought to discover novel genes contributing to LOAD risk.

Methods

Whole-exome sequencing and genome-wide genotyping were performed on 11 affected individuals in an extended family with an apparent autosomal dominant pattern of LOAD. Variants of interest were then evaluated in a large cohort of LOAD cases and aged controls.

Results

We detected a single rare, nonsynonymous variant shared in all 11 LOAD individuals, a missense change in the tetratricopeptide repeat domain 3 (TTC3) gene. The missense variant, rs377155188 (p.S1038C), is predicted to be damaging. Affecteds-only multipoint linkage analysis demonstrated that this region of TTC3 has a LOD score of 2.66 in this family.

Conclusion

The TTC3 p.S1038C substitution may represent a segregating, rare LOAD risk variant. Previous studies have shown that TTC3 expression is consistently reduced in LOAD patients and negatively correlated with AD neuropathology and that TTC3 is a regulator of Akt signaling, a key pathway disrupted in LOAD. This study demonstrates how utilizing whole-exome sequencing in a large, multigenerational family with a high incidence of LOAD could reveal a novel candidate gene."xsd:string
http://purl.uniprot.org/citations/27066578http://purl.org/dc/terms/identifier"doi:10.1212/nxg.0000000000000041"xsd:string
http://purl.uniprot.org/citations/27066578http://purl.org/dc/terms/identifier"doi:10.1212/nxg.0000000000000041"xsd:string
http://purl.uniprot.org/citations/27066578http://purl.uniprot.org/core/author"Schellenberg G.D."xsd:string
http://purl.uniprot.org/citations/27066578http://purl.uniprot.org/core/author"Schellenberg G.D."xsd:string
http://purl.uniprot.org/citations/27066578http://purl.uniprot.org/core/author"Haines J.L."xsd:string
http://purl.uniprot.org/citations/27066578http://purl.uniprot.org/core/author"Haines J.L."xsd:string
http://purl.uniprot.org/citations/27066578http://purl.uniprot.org/core/author"Pericak-Vance M.A."xsd:string
http://purl.uniprot.org/citations/27066578http://purl.uniprot.org/core/author"Pericak-Vance M.A."xsd:string
http://purl.uniprot.org/citations/27066578http://purl.uniprot.org/core/author"Gilbert J.R."xsd:string
http://purl.uniprot.org/citations/27066578http://purl.uniprot.org/core/author"Gilbert J.R."xsd:string
http://purl.uniprot.org/citations/27066578http://purl.uniprot.org/core/author"Vance J.M."xsd:string
http://purl.uniprot.org/citations/27066578http://purl.uniprot.org/core/author"Vance J.M."xsd:string
http://purl.uniprot.org/citations/27066578http://purl.uniprot.org/core/author"Farrer L.A."xsd:string
http://purl.uniprot.org/citations/27066578http://purl.uniprot.org/core/author"Farrer L.A."xsd:string
http://purl.uniprot.org/citations/27066578http://purl.uniprot.org/core/author"Beecham G.W."xsd:string
http://purl.uniprot.org/citations/27066578http://purl.uniprot.org/core/author"Beecham G.W."xsd:string
http://purl.uniprot.org/citations/27066578http://purl.uniprot.org/core/author"Kohli M.A."xsd:string
http://purl.uniprot.org/citations/27066578http://purl.uniprot.org/core/author"Kohli M.A."xsd:string
http://purl.uniprot.org/citations/27066578http://purl.uniprot.org/core/author"Whitehead P.L."xsd:string
http://purl.uniprot.org/citations/27066578http://purl.uniprot.org/core/author"Whitehead P.L."xsd:string
http://purl.uniprot.org/citations/27066578http://purl.uniprot.org/core/author"Martin E.R."xsd:string
http://purl.uniprot.org/citations/27066578http://purl.uniprot.org/core/author"Martin E.R."xsd:string
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