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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
5
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pubmed:dateCreated |
2010-2-9
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pubmed:abstractText |
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.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/20028451-11708987,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20028451-11764085,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20028451-12074169,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20028451-12526812,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20028451-12928786,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20028451-15350962,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20028451-15494732,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20028451-16862115,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20028451-16862116,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20028451-16983685,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20028451-17804792,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20028451-17953663,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20028451-17984093,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20028451-18183624,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20028451-18314228,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20028451-18378771,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20028451-18565828,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20028451-18768919,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20028451-19020205,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20028451-19158106,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20028451-8784346,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20028451-9629852,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20028451-9636220,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20028451-9641683
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Arginine,
http://linkedlifedata.com/resource/pubmed/chemical/Cysteine,
http://linkedlifedata.com/resource/pubmed/chemical/Dithiothreitol,
http://linkedlifedata.com/resource/pubmed/chemical/GRN protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Green Fluorescent Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Intercellular Signaling Peptides...,
http://linkedlifedata.com/resource/pubmed/chemical/Pancreatic Elastase,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Tyrosine,
http://linkedlifedata.com/resource/pubmed/chemical/granulin precursor protein
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
1471-4159
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:volume |
112
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1305-15
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pubmed:dateRevised |
2011-7-25
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pubmed:meshHeading |
pubmed-meshheading:20028451-Animals,
pubmed-meshheading:20028451-Arginine,
pubmed-meshheading:20028451-Axons,
pubmed-meshheading:20028451-Brain,
pubmed-meshheading:20028451-Cell Enlargement,
pubmed-meshheading:20028451-Cell Line, Transformed,
pubmed-meshheading:20028451-Cysteine,
pubmed-meshheading:20028451-Dithiothreitol,
pubmed-meshheading:20028451-Embryo, Mammalian,
pubmed-meshheading:20028451-Enzyme-Linked Immunosorbent Assay,
pubmed-meshheading:20028451-Family Health,
pubmed-meshheading:20028451-Frontotemporal Dementia,
pubmed-meshheading:20028451-Gene Expression Regulation,
pubmed-meshheading:20028451-Genetic Predisposition to Disease,
pubmed-meshheading:20028451-Green Fluorescent Proteins,
pubmed-meshheading:20028451-Humans,
pubmed-meshheading:20028451-Intercellular Signaling Peptides and Proteins,
pubmed-meshheading:20028451-Motor Neurons,
pubmed-meshheading:20028451-Mutation,
pubmed-meshheading:20028451-Neurites,
pubmed-meshheading:20028451-Pancreatic Elastase,
pubmed-meshheading:20028451-RNA, Messenger,
pubmed-meshheading:20028451-Rats,
pubmed-meshheading:20028451-Rats, Wistar,
pubmed-meshheading:20028451-Transfection,
pubmed-meshheading:20028451-Tyrosine
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pubmed:year |
2010
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