Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C→T (Arg493X) mutation: an international initiative

Rosa Rademakers, Matt Baker, Jennifer Gass, Jennifer Adamson, Edward D. Huey, Parastoo Momeni, Salvatore Spina, Giovanni Coppola, Anna M. Karydas, Heather Stewart, Nancy Johnson, Ging Yuek Hsiung, Brendan Kelley, Karen Kuntz, Ellen Steinbart, Elisabeth McCarty Wood, Chang En Yu, Keith Josephs, Eric Sorenson, Kyle B. WomackSandra Weintraub, Stuart M. Pickering-Brown, Peter R. Schofield, William S. Brooks, Vivianna M. Van Deerlin, Julie Snowden, Christopher M. Clark, Andrew Kertesz, Kevin Boylan, Bernardino Ghetti, David Neary, Gerard D. Schellenberg, Thomas G. Beach, Marsel Mesulam, David Mann, Jordan Grafman, Ian R. Mackenzie, Howard Feldman, Thomas Bird, Ron Petersen, David Knopman, Bradley Boeve, Dan H. Geschwind, Bruce Miller, Zbigniew Wszolek, Carol Lippa, Eileen H. Bigio, Dennis Dickson, Neill Graff-Radford, Mike Hutton

Research output: Contribution to journalArticlepeer-review

177 Scopus citations

Abstract

Background: The progranulin gene (GRN) is mutated in 5-10% of patients with frontotemporal lobar degeneration (FTLD) and in about 20% of patients with familial FTLD. The most common mutation in GRN is Arg493X. We aimed to establish the contribution of this mutation to FTLD and related disorders. 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 ε4 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.

Original languageEnglish (US)
Pages (from-to)857-868
Number of pages12
JournalLancet Neurology
Volume6
Issue number10
DOIs
StatePublished - Oct 2007

Bibliographical note

Funding Information:
We thank the families who contributed samples that were crucial to this study. This work was supported by NIH grants P01 AG017216 and R01 AG026251 (to MH), R01 AG026938 (to DHG), P50 NS40256 (to DD and ZW), the Mayo Clinic ADRC (P50 AG16574, RP PI; to MH, BB, and RP), P30 AG10133 (to SS and BG), P30 AG13854 (to MM, SW, NJ, and EHB), P30 AG12300 (to KBW), P01 AG17586 (to VMVD and GDS), P50 AG05136 (to GDS), P50 AG03006 and P01 AG019724 (to BM), the California DHS #04-35522 (to DHG), the Mayo Clinic Research Foundation (to MH and DD), and the Robert and Clarice Smith Fellowship program (to RR). EDH and JG were supported by the intramural research program of the Institute of Neurological Disorders and Stroke (NINDS). The work of TGB at the Sun Health Research Institute is supported by the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center) and the Arizona Department of Health Services contract 211002. IRM and HF were funded by the Canadian Institutes of Health Research Operating Grant number 74580. CL was supported by the Potamkin Foundation. Our work was also supported by the Veterans Affairs Research Funds, the ACCORD study (to AK), the Pacific Alzheimer Research Foundation, the Medical Research Council (to SMPB), and the National Health and Medical Research Council (Australia) grants 282933, 300400, and 276401. This study used samples from patients with amyotrophic lateral sclerosis from the NINDS Human Genetics Resource Center DNA and Cell Line Repository ( http://ccr.coriell.org/ninds ). RR is a postdoctoral fellow of the Fund for Scientific Research Flanders. SS is in part supported by, and is a PhD student of, the Department of Neurological and Behavioral Sciences, University of Siena, Siena, Italy. We thank Richard Caselli for providing us with FTLD patients for this study. His work is supported by the NIH P30 AG19610 grant. We also thank Jillian J Kril, Glenda M Halliday, Clement Loy, and Ralph N Martins for their study and ascertainment of the family with FTLD in Sydney.

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

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