Abstract
Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24–3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-014-1298-7) contains supplementary material, which is available to authorized users.
Highlights
Frontotemporal lobar degeneration (FTLD) represents a heterogeneous group of progressive neurodegenerative dementias, caused by local atrophy of frontal and/or temporal lobes
We provide further evidence for a putative role of rare mutations in sequestosome 1 (SQSTM1) in the genetic etiology of FTLD and showed that, comparable to other FTLD/amyotrophic lateral sclerosis (ALS) genes, SQSTM1 mutations are associated with TDP-43 pathology
We considered all published datasets that were generated by full exonic sequencing of SQSTM1 in both FTLD patient and control groups [7, 17, 28] and included the data in a meta-analysis with the present study comprising mutant allele frequencies in 4,332 FTLD and 10,240 control alleles
Summary
Frontotemporal lobar degeneration (FTLD) represents a heterogeneous group of progressive neurodegenerative dementias, caused by local atrophy of frontal and/or temporal lobes. It is one of the most common forms of earlyonset dementia (EOD), with the majority of FTLD patients developing disease between 45 and 65 years. About 15 % of FTLD patients present with a motor neuron disease (MND) syndrome, most commonly amyotrophic lateral sclerosis (ALS). Like FTLD, ALS is a neurodegenerative disorder in which loss of motor neurons leads to progressive weakness of the voluntary muscles. FTLD and ALS show important genetic overlap with mutations identified in the same genes, e.g., the common G4C2 repeat expansion in the chromosome 9 open reading frame 72 gene (C9orf72) and less frequently, mutations in the valosin containing protein (VCP), fused in sarcoma (FUS), TAR DNA-binding protein (TARDBP) and ubiquilin 2 (UBQLN2) genes [5, 8, 30, 31, 37].
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