TY - JOUR
T1 - Characterization of novel progranulin gene variants in Italian patients with neurodegenerative diseases
AU - Bartoletti-Stella, Anna
AU - De Pasqua, Silvia
AU - Baiardi, Simone
AU - Bartolomei, Ilaria
AU - Mengozzi, Giacomo
AU - Orio, Giuseppe
AU - Pastorelli, Francesca
AU - Piras, Silvia
AU - Poda, Roberto
AU - Raggi, Alberto
AU - Maserati, Michelangelo Stanzani
AU - Tarozzi, Martina
AU - Liguori, Rocco
AU - Salvi, Fabrizio
AU - Parchi, Piero
AU - Capellari, Sabina
N1 - Funding Information:
Supported by the Italian Ministry of Research RFO, Fondazione del Monte, and Fondazione Gino Galletti grants to SC, PP, and RL and AIRAlzh Onlus-COOP Italia grants to ABS.
Publisher Copyright:
© 2020
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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.
KW - Frontotemporal dementia
KW - Neurodegenerative diseases
KW - Progranulin
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U2 - 10.1016/j.neurobiolaging.2020.05.004
DO - 10.1016/j.neurobiolaging.2020.05.004
M3 - Article
C2 - 32507413
AN - SCOPUS:85086046610
VL - 97
SP - 145.e7-145.e15
JO - Neurobiology of Aging
JF - Neurobiology of Aging
SN - 0197-4580
ER -