Missense mutation in GRN gene affecting RNA splicing and plasma progranulin level in a family affected by frontotemporal lobar degeneration

Simona Luzzi, Lara Colleoni, Paola Corbetta, Sara Baldinelli, Chiara Fiori, Francesca Girelli, Mauro Silvestrini, Paola Caroppo, Giorgio Giaccone, Fabrizio Tagliavini, Giacomina Rossi

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Gene coding for progranulin, GRN, is a major gene linked to frontotemporal lobar degeneration. While most of pathogenic GRN mutations are null mutations leading to haploinsufficiency, GRN missense mutations do not have an obvious pathogenicity, and only a few have been revealed to act through different pathogenetic mechanisms, such as cytoplasmic missorting, protein degradation, and abnormal cleavage by elastase. The aim of this study was to disclose the pathogenetic mechanisms of the GRN A199V missense mutation, which was previously reported not to alter physiological progranulin features but was associated with a reduced plasma progranulin level. After investigating the family pedigree, we performed genetic and biochemical analysis on its members and performed RNA expression studies. We found that the mutation segregates with the disease and discovered that its pathogenic feature is the alteration of GRN mRNA splicing, actually leading to haploinsufficiency. Thus, when facing with a missense GRN mutation, its pathogenetic effects should be investigated, especially if associated with low plasma progranulin levels, to determine its nature of either benign polymorphism or pathogenic mutation.

Original languageEnglish
Pages (from-to)214.e1-214.e6
JournalNeurobiology of Aging
Volume54
DOIs
Publication statusPublished - Jun 1 2017

Fingerprint

Frontotemporal Lobar Degeneration
RNA Splicing
Missense Mutation
Haploinsufficiency
Mutation
Genes
Pancreatic Elastase
Pedigree
Proteolysis
Virulence
Molecular Biology
RNA
Messenger RNA

Keywords

  • Frontotemporal lobar degeneration
  • GRN
  • Mutation
  • Progranulin
  • RNA
  • Splicing

ASJC Scopus subject areas

  • Neuroscience(all)
  • Ageing
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Missense mutation in GRN gene affecting RNA splicing and plasma progranulin level in a family affected by frontotemporal lobar degeneration. / Luzzi, Simona; Colleoni, Lara; Corbetta, Paola; Baldinelli, Sara; Fiori, Chiara; Girelli, Francesca; Silvestrini, Mauro; Caroppo, Paola; Giaccone, Giorgio; Tagliavini, Fabrizio; Rossi, Giacomina.

In: Neurobiology of Aging, Vol. 54, 01.06.2017, p. 214.e1-214.e6.

Research output: Contribution to journalArticle

Luzzi, Simona ; Colleoni, Lara ; Corbetta, Paola ; Baldinelli, Sara ; Fiori, Chiara ; Girelli, Francesca ; Silvestrini, Mauro ; Caroppo, Paola ; Giaccone, Giorgio ; Tagliavini, Fabrizio ; Rossi, Giacomina. / Missense mutation in GRN gene affecting RNA splicing and plasma progranulin level in a family affected by frontotemporal lobar degeneration. In: Neurobiology of Aging. 2017 ; Vol. 54. pp. 214.e1-214.e6.
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