期刊
HUMAN MOLECULAR GENETICS
卷 15, 期 20, 页码 2988-3001出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddl241
关键词
-
资金
- Medical Research Council [G0400356] Funding Source: Medline
- NIA NIH HHS [P01 AG 017216, R01 AG 023195, P50 AG 16574, AG 12300, R01 AG 026251, P30 AG 13854, AG 024030, P30 AG 19610] Funding Source: Medline
- NIMH NIH HHS [MH/NS 31862] Funding Source: Medline
- NINDS NIH HHS [P50 NS 40256-06] Funding Source: Medline
- Medical Research Council [G0400356] Funding Source: researchfish
- MRC [G0400356] Funding Source: UKRI
Null mutations in the progranulin gene (PGRN) were recently reported to cause tau-negative frontotemporal dementia linked to chromosome 17. We assessed the genetic contribution of PGRN mutations in an extended population of patients with frontotemporal lobar degeneration (FTLD) (N=378). Mutations were identified in 10% of the total FTLD population and 23% of patients with a positive family history. This mutation frequency dropped to 5% when analysis was restricted to an unbiased FTLD subpopulation (N=167) derived from patients referred to Alzheimer's Disease Research Centers (ADRC). Among the ADRC patients, PGRN mutations were equally frequent as mutations in the tau gene (MAPT). We identified 23 different pathogenic PGRN mutations, including a total of 21 nonsense, frameshift and splice-site mutations that cause premature termination of the coding sequence and degradation of the mutant RNA by nonsense-mediated decay. We also observed an unusual splice-site mutation in the exon 1 5' splice site, which leads to loss of the Kozac sequence, and a missense mutation in the hydrophobic core of the PGRN signal peptide. Both mutations revealed novel mechanisms that result in loss of functional PGRN. One mutation, c.1477C > T (p.Arg493X), was detected in eight independently ascertained familial FTLD patients who were shown to share a common extended haplotype over the PGRN genomic region. Clinical examination of patients with PGRN mutations revealed highly variable onset ages with language dysfunction as a common presenting symptom. Neuropathological examination showed FTLD with ubiquitin-positive cytoplasmic and intranuclear inclusions in all PGRN mutation carriers.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据