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 journalArticle

163 Citations (Scopus)

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
Pages (from-to)857-868
Number of pages12
JournalThe Lancet Neurology
Volume6
Issue number10
DOIs
StatePublished - Oct 2007

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Frontotemporal Lobar Degeneration
Haploinsufficiency
Mutation
Haplotypes
Age of Onset
Genes
Microtubule-Associated Proteins
Alleles
Apolipoproteins E
Single Nucleotide Polymorphism
Linear Models
Primary Progressive Aphasia
Genotype
Regression Analysis
Apolipoprotein E4
Frontotemporal Dementia
Neurofibrillary Tangles
Penetrance
Memory Disorders
DNA-Binding Proteins

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

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

In: The Lancet Neurology, Vol. 6, No. 10, 10.2007, p. 857-868.

Research output: Contribution to journalArticle

Rademakers, R, Baker, M, Gass, J, Adamson, J, Huey, ED, Momeni, P, Spina, S, Coppola, G, Karydas, AM, Stewart, H, Johnson, N, Hsiung, GY, Kelley, B, Kuntz, K, Steinbart, E, Wood, EM, Yu, CE, Josephs, K, Sorenson, E, Womack, KB, Weintraub, S, Pickering-Brown, SM, Schofield, PR, Brooks, WS, Van Deerlin, VM, Snowden, J, Clark, CM, Kertesz, A, Boylan, K, Ghetti, B, Neary, D, Schellenberg, GD, Beach, TG, Mesulam, M, Mann, D, Grafman, J, Mackenzie, IR, Feldman, H, Bird, T, Petersen, R, Knopman, D, Boeve, B, Geschwind, DH, Miller, B, Wszolek, Z, Lippa, C, Bigio, EH, Dickson, D, Graff-Radford, N & Hutton, M 2007, 'Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C→T (Arg493X) mutation: an international initiative', The Lancet Neurology, vol. 6, no. 10, pp. 857-868. https://doi.org/10.1016/S1474-4422(07)70221-1
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. / Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C→T (Arg493X) mutation : an international initiative. In: The Lancet Neurology. 2007 ; Vol. 6, No. 10. pp. 857-868.
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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.",
author = "Rosa Rademakers and Matt Baker and Jennifer Gass and Jennifer Adamson and Huey, {Edward D.} and Parastoo Momeni and Salvatore Spina and Giovanni Coppola and Karydas, {Anna M.} and Heather Stewart and Nancy Johnson and Hsiung, {Ging Yuek} and Brendan Kelley and Karen Kuntz and Ellen Steinbart and Wood, {Elisabeth McCarty} and Yu, {Chang En} and Keith Josephs and Eric Sorenson and Womack, {Kyle B.} and Sandra Weintraub and Pickering-Brown, {Stuart M.} and Schofield, {Peter R.} and Brooks, {William S.} and {Van Deerlin}, {Vivianna M.} and Julie Snowden and Clark, {Christopher M.} and Andrew Kertesz and Kevin Boylan and Bernardino Ghetti and David Neary and Schellenberg, {Gerard D.} and Beach, {Thomas G.} and Marsel Mesulam and David Mann and Jordan Grafman and Mackenzie, {Ian R.} and Howard Feldman and Thomas Bird and Ron Petersen and David Knopman and Bradley Boeve and Geschwind, {Dan H.} and Bruce Miller and Zbigniew Wszolek and Carol Lippa and Bigio, {Eileen H.} and Dennis Dickson and Neill Graff-Radford and Mike Hutton",
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TY - JOUR

T1 - Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C→T (Arg493X) mutation

T2 - an international initiative

AU - Rademakers, Rosa

AU - Baker, Matt

AU - Gass, Jennifer

AU - Adamson, Jennifer

AU - Huey, Edward D.

AU - Momeni, Parastoo

AU - Spina, Salvatore

AU - Coppola, Giovanni

AU - Karydas, Anna M.

AU - Stewart, Heather

AU - Johnson, Nancy

AU - Hsiung, Ging Yuek

AU - Kelley, Brendan

AU - Kuntz, Karen

AU - Steinbart, Ellen

AU - Wood, Elisabeth McCarty

AU - Yu, Chang En

AU - Josephs, Keith

AU - Sorenson, Eric

AU - Womack, Kyle B.

AU - Weintraub, Sandra

AU - Pickering-Brown, Stuart M.

AU - Schofield, Peter R.

AU - Brooks, William S.

AU - Van Deerlin, Vivianna M.

AU - Snowden, Julie

AU - Clark, Christopher M.

AU - Kertesz, Andrew

AU - Boylan, Kevin

AU - Ghetti, Bernardino

AU - Neary, David

AU - Schellenberg, Gerard D.

AU - Beach, Thomas G.

AU - Mesulam, Marsel

AU - Mann, David

AU - Grafman, Jordan

AU - Mackenzie, Ian R.

AU - Feldman, Howard

AU - Bird, Thomas

AU - Petersen, Ron

AU - Knopman, David

AU - Boeve, Bradley

AU - Geschwind, Dan H.

AU - Miller, Bruce

AU - Wszolek, Zbigniew

AU - Lippa, Carol

AU - Bigio, Eileen H.

AU - Dickson, Dennis

AU - Graff-Radford, Neill

AU - Hutton, Mike

PY - 2007/10

Y1 - 2007/10

N2 - 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.

AB - 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.

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