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

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...

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Veröffentlicht in:Neurobiology of aging Jg. 38; S. 215.e1 - 215.e12
Hauptverfasser: Karch, Celeste M., Ezerskiy, Lubov, Redaelli, Veronica, Giovagnoli, Anna Rita, Tiraboschi, Pietro, Pelliccioni, Giuseppe, Pelliccioni, Paolo, Kapetis, Dimos, D'Amato, Ilaria, Piccoli, Elena, Ferretti, Maria Giulia, Tagliavini, Fabrizio, Rossi, Giacomina
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Elsevier Inc 01.02.2016
Schlagworte:
Adult
Aged
Aged, 80 and over
Cellobiose - analogs & derivatives
Cohort Studies
Female
Frontotemporal lobar degeneration
Frontotemporal Lobar Degeneration - genetics
Frontotemporal Lobar Degeneration - pathology
Functional analysis
Gene Dosage
Genetic Association Studies
GRN
HEK293 Cells
Humans
Intercellular Signaling Peptides and Proteins - analysis
Intercellular Signaling Peptides and Proteins - genetics
Internal Medicine
Middle Aged
Mutation
Mutation, Missense - genetics
Neurology
Pathogenetic
Progranulin
Progranulins
Frontotemporal lobar degeneration
GRN
Functional analysis
Progranulin
Mutation
Pathogenetic
ISSN:0197-4580, 1558-1497, 1558-1497
Online-Zugang:Volltext
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Zusammenfassung: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.
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ISSN:0197-4580
1558-1497
1558-1497
DOI:10.1016/j.neurobiolaging.2015.10.029