Fast track — ArticlesPhenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C→T (Arg493X) mutation: an international initiative
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.
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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
References (37)
- et al.
Conversion of proepithelin to epithelins: roles of SLPI and elastase in host defense and wound repair
Cell
(2002) - et al.
Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick's Disease
Arch Neurol
(2001) - et al.
Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria
Neurology
(1998) - et al.
Frontotemporal dementia
Semin Neurol
(2007) - et al.
The genetic and pathological classification of familial frontotemporal dementia
Arch Neurol
(2001) - et al.
Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
Science
(2006) Missense and splice site mutations in tau associated with FTDP-17: multiple pathogenic mechanisms
Neurology
(2001)- et al.
Tau is a candidate gene for chromosome 17 frontotemporal dementia
Ann Neurol
(1998) - et al.
Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments
Proc Natl Acad Sci U S A
(1997) - et al.
A family with tau-negative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17
Brain
(2006)
Tau negative frontal lobe dementia at 17q21: significant finemapping of the candidate region to a 4.8 cM interval
Mol Psychiatry
Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study
Brain
A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD
Brain
Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17
Nature
Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21
Nature
Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration
Hum Mol Genet
Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesis
J Mol Med
Progranulin in frontotemporal lobar degeneration and neuroinflammation
J Neuroinflammation
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