Reduced secretion and altered proteolytic processing caused by missense mutations in progranulin
Neurobiol Aging. 2016 Mar;39:220.e17-26
Christina Van Broeckhoven
|Type of Publication:||Journal Article|
Progranulin (GRN) is a secreted growth factor involved in various cellular functions and loss-of function mutations are a major cause of frontotemporal lobar degeneration (FTLD) with TDP-43 positive pathology. The majority of FTLD-related GRN mutations are nonsense mutations resulting in reduced GRN expression. Non-synonymous GRN missense mutations have been described as risk factor for neurodegenerative brain diseases, but their pathogenic nature remains largely elusive. We identified a double missense mutation in GRN leading to amino acid changes p.D33E and p.G35R in a FTLD patient from Turkish origin. Biochemical and cell biological analysis of the double-mutation together with two sofar uncharacterised GRN missense mutations (p.C105R and p.V514M) revealed a reduced secretion efficiency of the GRN p.D33E/p.G35R and p.C105R proteins. Furthermore, loss of the conserved cysteine residue affects protein folding and altered proteolytic processing by neutrophil elastase and proteinase 3. Our data indicate that the described variants may cause a loss-of-function, albeit to a lesser extent than GRN null mutations, and hence could be considered as low penetrant risk factors for neurodegenerative diseases.
Figure 1: GRN missense mutations affect progranulin secretion