The spectrum of mutations in progranulin: a collaborative study screening 545 cases of neurodegeneration

Abstract

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.

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

Design: Case-control study.

Setting: Clinical and neuropathology dementia research studies at 8 academic centers.

Participants: 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.

Main outcome measures: 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.

Figure 1

Neuropathological results of case ARC62 with GRN c.1414-16_1590del mutation. Photomicrographs of middle frontal gyrus showed extensive astrogliosis of cortex and less so of underlying white matter (A, hematoxylin-eosin, original magnification ×100; B, glial fibrillary acidic protein, original magnification ×40), extensive tau immunoreactivity in gray and white matter (C, tau2, original magnification ×100; gray matter above dotted line), a cortical “tufted” astrocyte (D, tau2 immunohistochemistry, original magnification ×400), and cytoplasmic intraneuronal inclusions that were immunoreactive for TDP-43 (E and F, original magnification ×600) and ubiquitin (G, original magnification ×600). Similar cytoplasmic inclusions immunoreactive for ubiquitinated TAR DNA binding protein and ubiquitin (H, original magnification ×600) were present in the granule neurons of the dentate gyrus of hippocampus.

Figure 2

GRN expressed sequence tags (ESTs) with alternatively spliced exons. The EST data were extracted from University of California Santa Cruz genome browser (Genome Bioinformatics Group). RefSeq indicates reference sequence.