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Title | Segregation of a rare TTC3 variant in an extended family with late-onset Alzheimer disease. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Kohli MA, Cukier HN, Hamilton-Nelson KL, Rolati S, Kunkle BW, Whitehead PL, Züchner SL, Farrer LA, Martin ER, Beecham GW, Haines JL, Vance JM, Cuccaro ML, Gilbert JR, Schellenberg GD, Carney RM, Pericak-Vance MA |
Journal | Neurol Genet |
Volume | 2 |
Issue | 1 |
Pagination | e41 |
Date Published | 2016 Feb |
ISSN | 2376-7839 |
Abstract | 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. |
DOI | 10.1212/NXG.0000000000000041 |
Alternate Journal | Neurol Genet |
PubMed ID | 27066578 |
PubMed Central ID | PMC4817909 |
Grant List | P30 AG013846 / AG / NIA NIH HHS / United States U01 AG032984 / AG / NIA NIH HHS / United States |