Pathogenic cysteine mutations affect progranulin function and production of mature granulins.
Frontotemporal dementia with ubiquitin-positive inclusions (FTLD-U) can be caused by mutations in the progranulin gene (GRN). Progranulin (PGRN) is a cysteine-rich growth factor, which is proteolytically cleaved by elastase to produce several granulins (GRNs). All FTLD-U mutations in GRN characterized to date result in reduced secreted PGRN protein. We recently reported a Spanish family with progressive non-fluent aphasia and dementia in which a novel C521Y mutation segregates with disease. A second cysteine mutation (C139R) has also been reported to be disease specific. Allele-specific mRNA expression assays in brain reveal that the C521Y mutant allele is expressed at similar levels to the wild-type allele. Furthermore, plasma PGRN levels in C521Y carriers are comparable with non-carrier family relatives, suggesting that the mutation does not affect PGRN protein expression and secretion in vivo. Despite normal PGRN levels C521Y and C139R mutant GRNs show reduced neurite growth-stimulating activity in vitro. Further study revealed that these mutations also cause impaired cleavage of PGRN by elastase. Our data suggest that these mutations affect the function of full-length PGRN as well as elastase cleavage of PGRN into GRNs, leading to neurodegeneration.
Wang
Jun
J
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
Van Damme
Philip
P
Cruchaga
Carlos
C
Gitcho
Michael A
MA
Vidal
Jose Manuel
JM
Seijo-Martínez
Manuel
M
Wang
Lei
L
Wu
Jane Y
JY
Robberecht
Wim
W
Goate
Alison
A
D000818:Animals; D001120:Arginine / Q000235:genetics; D001369:Axons / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000473:pathology; D049108:Cell Enlargement; D002461:Cell Line, Transformed; D003545:Cysteine / Q000235:genetics*; D004229:Dithiothreitol / Q000494:pharmacology; D004622:Embryo, Mammalian; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005192:Family Health; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D020022:Genetic Predisposition to Disease; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000502:physiology*; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D016501:Neurites; D010196:Pancreatic Elastase / Q000494:pharmacology; D000077153:Progranulins; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection; D014443:Tyrosine / Q000235:genetics
C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D012333:RNA, Messenger; D049452:Green Fluorescent Proteins; D014443:Tyrosine; D001120:Arginine; D010196:Pancreatic Elastase; D003545:Cysteine; D004229:Dithiothreitol