Missense mutations in progranulin gene associated with frontotemporal lobar degeneration: study of pathogenetic features.

Autor: Karch CM; Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA; Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St Louis, MO, USA., Ezerskiy L; Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA., Redaelli V; Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy., Giovagnoli AR; Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy., Tiraboschi P; Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy., Pelliccioni G; Division of Neurology, Geriatric Hospital, INRCA-IRCCS, Ancona, Italy., Pelliccioni P; Division of Neurology, Geriatric Hospital, INRCA-IRCCS, Ancona, Italy., Kapetis D; Bioinformatics Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy., D'Amato I; Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy., Piccoli E; Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy., Ferretti MG; Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy., Tagliavini F; Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy., Rossi G; Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy. Electronic address: grossi@istituto-besta.it.
Jazyk: angličtina
Zdroj: Neurobiology of aging [Neurobiol Aging] 2016 Feb; Vol. 38, pp. 215.e1-215.e12. Date of Electronic Publication: 2015 Nov 02.
DOI: 10.1016/j.neurobiolaging.2015.10.029
Abstrakt: GRN, the gene coding for the progranulin (PGRN) protein, was recognized as a gene linked to frontotemporal lobar degeneration (FTLD). The first mutations identified were null mutations giving rise to haploinsufficiency. Missense mutations were subsequently detected, but only a small subset has been functionally investigated. We identified missense mutations (C105Y, A199V, and R298H) in FTLD cases with family history and/or with low plasma PGRN levels. The aim of this study was to determine their pathogenicity. We performed functional studies, analyzing PGRN expression, secretion, and cleavage by elastase. GRN C105Y affected both secretion and elastase cleavage, likely representing a pathogenic mutation. GRN A199V did not alter the physiological properties of PGRN and GRN R298H produced only moderate effects on PGRN secretion, indicating that their pathogenicity is uncertain. In the absence of strong segregation data and neuropathological examinations, genetic, biomarker, and functional studies can be applied to an algorithm to assess the likelihood of pathogenicity for a mutation. This information can improve our understanding of the complex mechanisms by which GRN mutations lead to FTLD.
(Copyright © 2016 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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