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

Publication date: Available online 20 February 2017
Source:Neurobiology of Aging
Author(s): Simona Luzzi, Lara Colleoni, Paola Corbetta, Sara Baldinelli, Chiara Fiori, Francesca Girelli, Mauro Silvestrini, Paola Caroppo, Giorgio Giaccone, Fabrizio Tagliavini, Giacomina Rossi
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 mis-sorting, 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, in order to determine its nature of either benign polymorphism or pathogenic mutation.



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