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 language | English |
|---|---|
| Pages (from-to) | 215.e1-12 |
| Journal | Neurobiology of Aging |
| Volume | 38 |
| DOIs | |
| Publication status | Published - Feb 2016 |
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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 journal › Article
}
TY - JOUR
T1 - Missense mutations in progranulin gene associated with frontotemporal lobar degeneration
T2 - study of pathogenetic features
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.
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Cellobiose
KW - Cohort Studies
KW - Female
KW - Frontotemporal Lobar Degeneration
KW - Gene Dosage
KW - Genetic Association Studies
KW - HEK293 Cells
KW - Humans
KW - Intercellular Signaling Peptides and Proteins
KW - Middle Aged
KW - Mutation, Missense
KW - Case Reports
KW - Journal Article
KW - Research Support, N.I.H., Extramural
U2 - 10.1016/j.neurobiolaging.2015.10.029
DO - 10.1016/j.neurobiolaging.2015.10.029
M3 - Article
C2 - 26652843
VL - 38
SP - 215.e1-12
JO - Neurobiology of Aging
JF - Neurobiology of Aging
SN - 0197-4580
ER -