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

Celeste M. Karch, Lubov Ezerskiy, Veronica Redaelli, Anna Rita Giovagnoli, Pietro Tiraboschi, Giuseppe Pelliccioni, Paolo Pelliccioni, Dimos Kapetis, Ilaria D'Amato, Elena Piccoli, Maria Giulia Ferretti, Fabrizio Tagliavini, Giacomina Rossi

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)215.e1-12
JournalNeurobiology of Aging
Volume38
DOIs
Publication statusPublished - Feb 2016

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Frontotemporal Lobar Degeneration
Missense Mutation
Mutation
Virulence
Genes
Pancreatic Elastase
Haploinsufficiency
Biomarkers
Proteins

Keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • Cellobiose
  • Cohort Studies
  • Female
  • Frontotemporal Lobar Degeneration
  • Gene Dosage
  • Genetic Association Studies
  • HEK293 Cells
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Middle Aged
  • Mutation, Missense
  • Case Reports
  • Journal Article
  • Research Support, N.I.H., Extramural

Cite this

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

In: Neurobiology of Aging, Vol. 38, 02.2016, p. 215.e1-12.

Research output: Contribution to journalArticle

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. / Missense mutations in progranulin gene associated with frontotemporal lobar degeneration : study of pathogenetic features. In: Neurobiology of Aging. 2016 ; Vol. 38. pp. 215.e1-12.
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T1 - Missense mutations in progranulin gene associated with frontotemporal lobar degeneration

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AU - Karch, Celeste M.

AU - Ezerskiy, Lubov

AU - Redaelli, Veronica

AU - Giovagnoli, Anna Rita

AU - Tiraboschi, Pietro

AU - Pelliccioni, Giuseppe

AU - Pelliccioni, Paolo

AU - Kapetis, Dimos

AU - D'Amato, Ilaria

AU - Piccoli, Elena

AU - Ferretti, Maria Giulia

AU - Tagliavini, Fabrizio

AU - Rossi, Giacomina

N1 - Copyright © 2016 Elsevier Inc. All rights reserved.

PY - 2016/2

Y1 - 2016/2

N2 - 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.

AB - 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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KW - Cohort Studies

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KW - Gene Dosage

KW - Genetic Association Studies

KW - HEK293 Cells

KW - Humans

KW - Intercellular Signaling Peptides and Proteins

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KW - Mutation, Missense

KW - Case Reports

KW - Journal Article

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JO - Neurobiology of Aging

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