Elsevier

The Lancet Neurology

Volume 6, Issue 10, October 2007, Pages 857-868
The Lancet Neurology

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

https://doi.org/10.1016/S1474-4422(07)70221-1Get rights and content

Summary

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 ɛ4 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.

Introduction

Neurodegenerative disorders that are characterised by atrophy of the prefrontal and anterior temporal lobes are collectively referred to as frontotemporal lobar degeneration (FTLD).1, 2 FTLD is the second most common type of early-onset neurodegenerative dementia after Alzheimer's disease, accounting for 5–10% of cases of dementia and 10–20% of dementia cases with onset before 65 years.3 The most common presenting symptoms are behavioural and personality changes, such as disinhibition, perseveration, and emotional blunting. Language dysfunction and cognitive impairments that lead to deficits in executive functions also occur. Three clinical FTLD subtypes have been defined: behavioural variant frontotemporal dementia (FTD-bv), primary progressive aphasia, and FTLD with motor neuron disease. Primary progressive aphasia has been subdivided into progressive non-fluent aphasia and semantic dementia. Patients with FTLD are also divided into two main subgroups on the basis of immunohistochemical staining and the distribution of intracellular inclusions: those with tau-positive pathology, and those who have FTLD with inclusions that are ubiquitin-positive, but tau-negative and synuclein-negative (FTLDU).4 The TAR DNA-binding protein 43 (TARDBP or TDP43) has been identified as a major protein of the tau-negative inclusions in FTLDU.5

FTLD has a high familial incidence, with up to 50% of patients reported to have a family history of a similar dementia. In 1998, mutations in the microtubule-associated protein tau gene (MAPT) were identified in families with tau-positive FTLD who present with dementia and parkinsonism linked to chromosome 17q21 (FTDP17).6, 7, 8 Familial FTLDU pathology with ubiquitin-positive neuronal cytoplasmic and intranuclear inclusions has also been linked to 17q21, but not to mutations in MAPT.9, 10, 11, 12 Our discovery of mutations in the progranulin gene (GRN), which is located close to MAPT, can explain the genetic heterogeneity in patients with FTDP17.13, 14

Mutations in GRN are a major cause of FTLD, and they account for 5–10% of FTLD cases worldwide.15 In subpopulations of patients with familial FTLD or populations enriched for patients with FTLDU, the GRN mutation frequency can be up to 25%. 44 different pathogenic GRN mutations have been reported in 82 families, and all are expected to cause 50% loss of functional progranulin, and so haploinsufficiency (Alzheimer Disease and Frontotemporal Dementia Mutation Database, http://www.molgen.ua.ac.be/FTDmutations/).

Progranulin (predicted molecular weight 68 kDa) is a secreted factor that can be cleaved by an elastase-like activity into 6-kDa cysteine-rich fragments called granulins.16, 17 Both progranulin and the granulins are important in tissue remodelling.18 In peripheral tissues, progranulin is involved in development, wound repair, and inflammation, by activating signalling cascades that control cell-cycle progression and cell motility.19 In the brain, where progranulin is expressed in both neurons and microglia, the functions of this mitogenic factor have not been studied extensively. However, the finding that reduced concentrations of progranulin can induce neurodegeneration in patients with FTLD implicates progranulin in neuronal survival.13, 14

The most commonly reported mutation in GRN is 1477C→T (Arg493X). This mutation lies in exon 11 and has been identified in 14 genealogically unrelated families with FTLD.15, 20, 21, 22, 23 We aimed to establish the contribution of Arg493X to the development of FTLD and related disorders by analysing patients with various neurodegenerative diseases, and by doing detailed clinicopathological and genetic analyses in 30 unrelated Arg493X families identified in an international study.

Section snippets

Participants

An initial cohort of 3405 genealogically unrelated patients with neurodegenerative disorders as diagnosed clinically, pathologically, or both (table 1) was analysed for the Arg493X mutation in GRN. This study group consisted of patients from four different series (panel): the Brain Bank of Mayo Clinic Jacksonville, FL, USA (MCJ Brain Bank series); the Olmsted County community-based dementia series, also known as the Alzheimer's Disease Patient Registry (ADPR series); the ADRC series, which

Results

Table 1 shows the origins and primary diagnoses of the 3405 patients in the initial study cohort. We detected the Arg493X mutation in eight patients from the Mayo Clinic FTLD series that we previously analysed for GRN mutations,15 and in a further eight previously unreported patients with FTLD. The Arg493X mutation was thus identified in 16 (2%) of the 731 patients with FTLD. We recorded no Arg493X mutations in the 2674 patients affected by neurodegeneration other than FTLD. Of the patients

Discussion

We identified the Arg493X mutation in 2% of patients with FTLD. As expected, the frequency of Arg493X was much higher in groups of patients from tertiary referral centres, which include a higher proportion of patients with familial FTLD and FTLDU, than in the unbiased, sequential ADRC series (4% vs 1%). Previous complete GRN sequencing analyses in 378 of these patients revealed an overall GRN mutation frequency of 10·5%, and a similarly greater mutation frequency in the tertiary referral series

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