期刊
NEUROBIOLOGY OF AGING
卷 97, 期 -, 页码 -出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2020.05.004
关键词
Progranulin; Frontotemporal dementia; Neurodegenerative diseases
资金
- Italian Ministry of Research RFO
- Fondazione del Monte
- Fondazione Gino Galletti
- AIRAlzh Onlus-COOP Italia grants
Loss-of-function mutations in the gene encoding for the protein progranulin (PGRN), GRN, are a major cause in frontotemporal lobar degeneration. However, genetic variations in GRN have also been linked to other neurodegenerative diseases. In a cohort of Italian patients affected by various neurodegenerative disorders, 12 different pathogenic/likely pathogenic variants were identified.
Loss-of-function mutations in the gene encoding for the protein progranulin (PGRN), GRN, are one of the major genetic abnormalities involved in frontotemporal lobar degeneration. However, genetic variations, mainly missense, in GRN have also been linked to other neurodegenerative diseases. We found 12 different pathogenic/likely pathogenic variants in 21 patients identified in a cohort of Italian patients affected by various neurodegenerative disorders. We detected the p.Thr272SerfsTer10 as the most frequent, followed by the c.1179+3A>G variant. We characterized the clinical phenotype of 12 patients from 3 pedigrees carrying the c.1179+3A>G variant, demonstrated the pathogenicity of this mutation, and detected other rarer variants causing haploinsufficiency (p.Met1?, c.709-2A>T, p.Gly79AspfsTer39). Finally, by applying bioinformatics, neuropathological, and biochemical studies, we characterized 6 missense/synonymous variants (p.Asp94His, p.Gly117Asp, p.Ala266Pro, p.Val279Val, p.Arg298His, p.Ala505Gly), including 4 previously unreported. The designation of variants is crucial for genetic counseling and the enrollment of patients in clinical studies. (C) 2020 Published by Elsevier Inc.
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