Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C-->T (Arg493X) mutation: an international initiative.
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Rademakers Rosa, Baker Matt, Gass Jennifer, Adamson Jennifer, Huey Edward D, Momeni Parastoo, Spina Salvatore, Coppola Giovanni, Karydas Anna M, Stewart Heather, Johnson Nancy, Hsiung Ging-Yuek, Kelley Brendan, Kuntz Karen, Steinbart Ellen, Wood Elisabeth McCarty, Yu Chang-En, Josephs Keith, Sorenson Eric, Womack Kyle B, Weintraub Sandra, Pickering-Brown Stuart M, Schofield Peter R, Brooks William S, Van Deerlin Vivianna M, Snowden Julie, Clark Christopher M, Kertesz Andrew, Boylan Kevin, Ghetti Bernardino, Neary David, Schellenberg Gerard D, Beach Thomas G, Mesulam Marsel, Mann David, Grafman Jordan, Mackenzie Ian R, Feldman Howard, Bird Thomas, Petersen Ron, Knopman David, Boeve Bradley, Geschwind Dan H, Miller Bruce, Wszolek Zbigniew, Lippa Carol, Bigio Eileen H, Dickson Dennis, Graff-Radford Neill, Hutton Mike
Аннотация
METHODS: We measured the frequency of Arg493X in 3405 unrelated patients with various neurodegenerative diseases using Taqman single-nucleotide polymorphism (SNP) genotyping. Clinicopathological characterisation and shared haplotype analysis were done for 30 families with FTLD who carry Arg493X. To investigate the effect of potential modifying loci, we did linear regression analyses with onset age as the covariate for GRN variants, for genotypes of the apolipoprotein E gene (APOE), and for haplotypes of the microtubule-associated protein tau gene (MAPT).
FINDINGS: Of 731 patients with FTLD, 16 (2%) carried Arg493X. This mutation was not detected in 2674 patients who did not have FTLD. In 37 patients with Arg493X from 30 families with FTLD, clinical diagnoses included frontotemporal dementia, primary progressive aphasia, corticobasal syndrome, and Alzheimer's disease. Range of onset age was 44-69 years. In all patients who came to autopsy (n=13), the pathological diagnosis was FTLD with neuronal inclusions that contained TAR DNA-binding protein or ubiquitin, but not tau. Neurofibrillary tangle pathology in the form of Braak staging correlated with overall neuropathology in the Arg493X carriers. Haplotype analyses suggested that Arg493X arose twice, with a single founder for 27 families. Linear regression analyses suggested that patients with SNP rs9897528 on their wild-type GRN allele have delayed symptom onset. Onset ages were not associated with the MAPT H1 or H2 haplotypes or APOE genotypes, but early memory deficits were associated with the presence of an APOE epsilon4 allele.
INTERPRETATION: Clinical heterogeneity is associated with GRN haploinsufficiency, and genetic variability on the wild-type GRN allele might have a role in the age-related disease penetrance of GRN mutations.