The spectrum of mutations in progranulin: a collaborative study screening 545 cases of neurodegeneration.
BACKGROUND
Mutation in the progranulin gene (GRN) can cause frontotemporal dementia (FTD). However, it is unclear whether some rare FTD-related GRN variants are pathogenic and whether neurodegenerative disorders other than FTD can also be caused by GRN mutations.


OBJECTIVE
To delineate the range of clinical presentations associated with GRN mutations and to define pathogenic candidacy of rare GRN variants.


METHODS
Case-control study.


METHODS
Clinical and neuropathology dementia research studies at 8 academic centers.


METHODS
Four hundred thirty-four patients with FTD, including primary progressive aphasia, semantic dementia, FTD/amyotrophic lateral sclerosis (ALS), FTD/motor neuron disease, corticobasal syndrome/corticobasal degeneration, progressive supranuclear palsy, Pick disease, dementia lacking distinctive histopathology, and pathologically confirmed cases of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U); and 111 non-FTD cases (controls) in which TDP-43 deposits were a prominent neuropathological feature, including subjects with ALS, Guam ALS and/or parkinsonism dementia complex, Guam dementia, Alzheimer disease, multiple system atrophy, and argyrophilic grain disease.


METHODS
Variants detected on sequencing of all 13 GRN exons and at least 80 base pairs of flanking introns, and their pathogenic candidacy determined by in silico and ex vivo splicing assays.


RESULTS
We identified 58 genetic variants that included 26 previously unknown changes. Twenty-four variants appeared to be pathogenic, including 8 novel mutations. The frequency of GRN mutations was 6.9% (30 of 434) of all FTD-spectrum cases, 21.4% (9 of 42) of cases with a pathological diagnosis of FTLD-U, 16.0% (28 of 175) of FTD-spectrum cases with a family history of a similar neurodegenerative disease, and 56.2% (9 of 16) of cases of FTLD-U with a family history.


CONCLUSIONS
Pathogenic mutations were found only in FTD-spectrum cases and not in other related neurodegenerative diseases. Haploinsufficiency of GRN is the predominant mechanism leading to FTD.
Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA 98108, USA. tomnroz@u.washington.edu
Chang-En
CE
Yu
Thomas D
TD
Bird
Lynn M
LM
Bekris
Thomas J
TJ
Montine
James B
JB
Leverenz
Ellen
E
Steinbart
Nichole M
NM
Galloway
Howard
H
Feldman
Randall
R
Woltjer
Carol A
CA
Miller
Elisabeth McCarty
EM
Wood
Murray
M
Grossman
Leo
L
McCluskey
Christopher M
CM
Clark
Manuela
M
Neumann
Adrian
A
Danek
Douglas R
DR
Galasko
Steven E
SE
Arnold
Alice
A
Chen-Plotkin
Anna
A
Karydas
Bruce L
BL
Miller
John Q
JQ
Trojanowski
Virginia M-Y
VM
Lee
Gerard D
GD
Schellenberg
Vivianna M
VM
Van Deerlin
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000145:classification* / Q000235:genetics*; D000077153:Progranulins; D022821:RNA Splice Sites / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism; D055815:Young Adult
C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D022821:RNA Splice Sites; D025801:Ubiquitin