Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/79352
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dc.contributor.authorDobson-Stone, C.en
dc.contributor.authorLuty, A.en
dc.contributor.authorThompson, E.en
dc.contributor.authorBlumbergs, P.en
dc.contributor.authorBrooks, W.en
dc.contributor.authorShort, C.en
dc.contributor.authorField, C.en
dc.contributor.authorPanegyres, P.en
dc.contributor.authorHecker, J.en
dc.contributor.authorSolski, J.en
dc.contributor.authorBlair, I.en
dc.contributor.authorFullerton, J.en
dc.contributor.authorHalliday, G.en
dc.contributor.authorSchofield, P.en
dc.contributor.authorKwok, J.en
dc.date.issued2013en
dc.identifier.citationActa Neuropathologica, 2013; 125(4):523-533en
dc.identifier.issn0001-6322en
dc.identifier.issn1432-0533en
dc.identifier.urihttp://hdl.handle.net/2440/79352-
dc.description.abstractNumerous families exhibiting both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) have been described, and although many of these have been shown to harbour a repeat expansion in C9ORF72, several C9ORF72-negative FTD-ALS families remain. We performed neuropathological and genetic analysis of a large European Australian kindred (Aus-12) with autosomal dominant inheritance of dementia and/or ALS. Affected Aus-12 members developed either ALS or dementia; some of those with dementia also had ALS and/or extrapyramidal features. Neuropathology was most consistent with frontotemporal lobar degeneration with type B TDP pathology, but with additional phosphorylated tau pathology consistent with corticobasal degeneration. Aus-12 DNA samples were negative for mutations in all known dementia and ALS genes, including C9ORF72 and FUS. Genome-wide linkage analysis provided highly suggestive evidence (maximum multipoint LOD score of 2.9) of a locus on chromosome 16p12.1–16q12.2. Affected individuals shared a chromosome 16 haplotype flanked by D16S3103 and D16S489, spanning 37.9 Mb, with a smaller suggestive disease haplotype spanning 24.4 Mb defined by recombination in an elderly unaffected individual. Importantly, this smaller region does not overlap with FUS. Whole-exome sequencing identified four variants present in the maximal critical region that segregate with disease. Linkage analysis incorporating these variants generated a maximum multipoint LOD score of 3.0. These results support the identification of a locus on chromosome 16p12.1–16q12.2 responsible for an unusual cluster of neurodegenerative phenotypes. This region overlaps with a separate locus on 16q12.1–q12.2 reported in an independent ALS family, indicating that this region may harbour a second major locus for FTD-ALS.en
dc.description.statementofresponsibilityCarol Dobson-Stone, Agnes A. Luty, Elizabeth M. Thompson, Peter Blumbergs, William S. Brooks, Cathy L. Short, Colin D. Field, Peter K. Panegyres, Jane Hecker, Jennifer A. Solski, Ian P. Blair, Janice M. Fullerton, Glenda M. Halliday, Peter R. Schofield, John B. J. Kwoken
dc.language.isoenen
dc.publisherSpringeren
dc.rights© The Author(s) 2013. This article is published with open access at Springerlink.comen
dc.subjectFrontotemporal dementia; Amyotrophic lateral sclerosis; Motor neuron disease; Corticobasal degeneration; Tau; TDP-43en
dc.titleFrontotemporal dementia-amyotrophic lateral sclerosis syndrome locus on chromosome 16p12.1-q12.2: genetic, clinical and neuropathological analysisen
dc.typeJournal articleen
dc.identifier.rmid0020124836en
dc.identifier.doi10.1007/s00401-013-1078-9en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/157209en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/630434en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/276401en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/510217en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/630428en
dc.identifier.pubid21579-
pubs.library.collectionPaediatrics publicationsen
pubs.verification-statusVerifieden
pubs.publication-statusPublisheden
Appears in Collections:Paediatrics publications

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