Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration
Author(s)
Type
Journal Article
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.
Date Issued
2014-09-01
Date Acceptance
2014-05-20
Citation
ACTA NEUROPATHOLOGICA, 2014, 128 (3), pp.397-410
ISSN
0001-6322
Publisher
SPRINGER
Start Page
397
End Page
410
Journal / Book Title
ACTA NEUROPATHOLOGICA
Volume
128
Issue
3
Copyright Statement
© 2014 The Author(s). Open Access. This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000340551900007&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Clinical Neurology
Neurosciences
Pathology
Neurosciences & Neurology
Sequestosome 1
SQSTM1
p62
FTLD
ALS
Rare variants
AMYOTROPHIC-LATERAL-SCLEROSIS
DIPEPTIDE-REPEAT PROTEINS
PAGET-DISEASE
DIAGNOSTIC-CRITERIA
GLIAL INCLUSIONS
BINDING PROTEIN
DEMENTIA
BONE
GENE
P62
Publication Status
Published
Date Publish Online
2014-06-05