Novel progranulin mutation detected in 2 patients with FTLD.
Frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions, and linkage to chromosome 17 was recently found to be caused by mutations in the progranulin (PGRN) gene. In this study, we screened a group of 51 FTLD patients for PGRN mutations and identified a novel exon 6 splice donor site deletion (IVS6+5_8delGTGA) in 2 unrelated patients. This mutation displayed an altered splicing pattern generating 2 aberrant transcripts and causing frameshifts of the coding sequence, premature termination codons, and a near absence of PGRN mRNA from the mutated alleles most likely through nonsense-mediated decay. The subsequent PGRN haploinsufficiency is consistent with previously described PGRN mutations. We present a molecular characterization of the IVS6+5_8delGTGA mutation and also describe clinical and neuropathologic features from the 2 patients carrying this PGRN mutation. From the screening of these 51 FTLD patients, we could also identify the earlier reported mutation Gln130fs, and several coding sequence variants that are most likely nonpathogenic.
Skoglund
Lena
L
Molecular Geriatrics, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
Matsui
Toshifumi
T
Freeman
Stefanie H
SH
Wallin
Anders
A
Blom
Elin S
ES
Frosch
Matthew P
MP
Growdon
John H
JH
Hyman
Bradley T
BT
Lannfelt
Lars
L
Ingelsson
Martin
M
Glaser
Anna
A
D000368:Aged; D004252:DNA Mutational Analysis; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D009154:Mutation; D000077153:Progranulins; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D012333:RNA, Messenger