Dataset Information

Segregation of a rare TTC3 variant in an extended family with late-onset Alzheimer disease.

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.

SUBMITTER: Kohli MA

PROVIDER: S-EPMC4817909 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Segregation of a rare TTC3 variant in an extended family with late-onset Alzheimer disease.

Kohli Martin A MA Cukier Holly N HN Hamilton-Nelson Kara L KL Rolati Sophie S Kunkle Brian W BW Whitehead Patrice L PL Züchner Stephan L SL Farrer Lindsay A LA Martin Eden R ER Beecham Gary W GW Haines Jonathan L JL Vance Jeffery M JM Cuccaro Michael L ML Gilbert John R JR Schellenberg Gerard D GD Carney Regina M RM Pericak-Vance Margaret A MA

Neurology. Genetics 20160114 1

<h4>Objective</h4>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.<h4>Methods</h4>Whole-exome sequencing and genome-wide genotyping were performed on 11 affected individuals in an extended family with an apparent autosomal dominant pattern of LOA ...[more]

PMID: 27066578

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Project description:ImportanceThe R47H variant in the triggering receptor expressed on myeloid cells 2 gene (TREM2), a modulator of the immune response of microglia, is a strong genetic risk factor for Alzheimer disease (AD) and possibly other neurodegenerative disorders.ObjectiveTo investigate a large family with late-onset AD (LOAD), in which R47H cosegregated with 75% of cases.Design, setting, and participantsThis study includes genetic and pathologic studies of families with LOAD from 1985 to 2014. A total of 131 families with LOAD (751 individuals) were included from the University of Washington Alzheimer Disease Research Center. To identify LOAD genes/risk factors in the LOAD123 family with 21 affected members and 12 autopsies, we sequenced 4 exomes. Candidate variants were tested for cosegregation with the disease. TREM2 R47H was genotyped in an additional 130 families with LOAD. We performed clinical and neuropathological assessments of patients with and without R47H and evaluated the variant's effect on brain pathology, cellular morphology, and expression of microglial markers.Main outcomes and measuresWe assessed the effect of TREM2 genotype on age at onset and disease duration. We compared Braak and Consortium to Establish a Registry for Alzheimer's Disease scores, presence of α-synuclein and TAR DNA-binding protein 43 aggregates, and additional vascular or Parkinson pathology in TREM2 R47H carriers vs noncarriers. Microglial activation was assessed by quantitative immunohistochemistry and morphometry.ResultsTwelve of 16 patients with AD in the LOAD123 family carried R47H. Eleven patients with dementia had apolipoprotein E 4 (ApoE4) and R47H genotypes. We also found a rare missense variant, D353N, in a nominated AD risk gene, unc-5 homolog C (UNC5C), in 5 affected individuals in the LOAD123 family. R47H carriers demonstrated a shortened disease duration (mean [SD], 6.7 [2.8] vs 11.1 [6.6] years; 2-tailed t test; P = .04) and more frequent α-synucleinopathy. The panmicroglial marker ionized calcium-binding adapter molecule 1 was decreased in all AD cases and the decrease was most pronounced in R47H carriers (mean [SD], in the hilus: 0.114 [0.13] for R47H_AD vs 0.574 [0.26] for control individuals; 2-tailed t test; P = .005 and vs 0.465 [0.32] for AD; P = .02; in frontal cortex gray matter: 0.006 [0.004] for R47H_AD vs 0.016 [0.01] for AD; P = .04 and vs 0.033 [0.013] for control individuals; P < .001). Major histocompatibility complex class II, a marker of microglial activation, was increased in all patients with AD (AD: 2.5, R47H_AD: 2.7, and control: 1.0; P < .01).Conclusions and relevanceOur results demonstrate a complex genetic landscape of LOAD, even in a single pedigree with an apparent autosomal dominant pattern of inheritance. ApoE4, TREM2 R47H, and rare variants in other genes, such as UNC5C D353N, are likely responsible for the notable occurrence of AD in this family. Our findings support the role of the TREM2 receptor in microglial clearance of aggregation-prone proteins that is compromised in R47H carriers and may accelerate the course of disease.

Dataset Information

Segregation of a rare TTC3 variant in an extended family with late-onset Alzheimer disease.

Publications

Segregation of a rare TTC3 variant in an extended family with late-onset Alzheimer disease.

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