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Molecular characterization of novel progranulin ( GRN ) mutations in frontotemporal dementia
Author(s) -
Mukherjee Odity,
Wang Jun,
Gitcho Michael,
Chakraverty Sumi,
TaylorReinwald Lisa,
Shears Shantia,
Kauwe John S.K.,
Norton Joanne,
Levitch Denise,
Bigio Eileen H.,
Hatanpaa Kimmo J.,
White Charles L.,
Morris John C.,
Cairns Nigel J.,
Goate Alison
Publication year - 2008
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20681
Subject(s) - frontotemporal dementia , biology , genetics , mutation , frontotemporal lobar degeneration , neuroscience , computational biology , dementia , gene , medicine , disease
Frontotemporal dementia (FTD) is a clinical term encompassing dementia characterized by the presence of two major phenotypes: 1) behavioral and personality disorder, and 2) language disorder, which includes primary progressive aphasia and semantic dementia. Recently, the gene for familial frontotemporal lobar degeneration (FTLD) with ubiquitin‐positive, tau‐negative inclusions (FTLD‐U) linked to chromosome 17 was cloned. In the present study, 62 unrelated patients from the Washington University Alzheimer's Disease Research Center and the Midwest Consortium for FTD with clinically diagnosed FTD and/or neuropathologically characterized cases of FTLD‐U with or without motor neuron disease (MND) were screened for mutations in the progranulin gene ( GRN ; also PGRN ). We discovered two pathogenic mutations in four families: 1) a single‐base substitution within the 3′ splice acceptor site of intron 6/exon 7 (g.5913A>G [IVS6–2A>G]) causing skipping of exon 7 and premature termination of the coding sequence (PTC); and 2) a missense mutation in exon 1 (g.4068C>A) introducing a charged amino acid in the hydrophobic core of the signal peptide at residue 9 (p.A9D). Functional analysis in mutation carriers for the splice acceptor site mutation revealed a 50% decrease in GRN mRNA and protein levels, supporting haploinsufficiency. In contrast, there was no significant difference in the total GRN mRNA between cases and controls carrying the p.A9D mutation. Further, subcellular fractionation and confocal microscopy indicate that although the mutant protein is expressed, it is not secreted, and appears to be trapped within an intracellular compartment, possibly resulting in a functional haploinsufficiency. Hum Mutat 29(4), 512–521, 2008. © 2008 Wiley‐Liss, Inc.