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Identification of novel alternative splicing events in the Huntingtin gene and assessment of the functional consequences using structural protein homology modelling

Hughes, Alis, Mort, Matthew Edwin, Elliston, Linda Anne, Thomas, Rhian M., Brooks, Simon Philip, Dunnett, Stephen Bruce and Jones, Lesley 2014. Identification of novel alternative splicing events in the Huntingtin gene and assessment of the functional consequences using structural protein homology modelling. Journal of Molecular Biology 426 (7) , pp. 1428-1438. 10.1016/j.jmb.2013.12.028

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Abstract

Huntington's disease (HD) is an inherited progressive neurodegenerative disorder caused by a pathological CAG trinucleotide repeat expansion in the large multi-exon gene, huntingtin (HTT). Although multiple pathogenic mechanisms have been proposed for HD, there is increasing interest in the RNA processing of the HTT gene. In mammals, most multi-exon genes are alternatively spliced; however, few alternative transcripts have been described for HTT. Given the numerous protein bands detected in mouse and human brain tissue by Western blotting using anti-huntingtin antibodies, we examined whether alternative splicing of HTT may account for some of these fragments. Using RT-PCR in mouse brain, we detected two novel splice variants of Htt that lacked the 111-bp exon 29 (Htt∆ex29) or retained a 57-bp portion of intron 28 (Htt+ 57in28) via use of a cryptic splice site. The alternative transcripts were present in wild-type and homozygous Hdh(Q150/Q150) mouse brain at all ages and in all brain regions and peripheral tissues studied. Differential splicing of Htt∆ex29 was found in the cerebellum of Hdh(Q150/Q150) mice with a significant reduction in transcript levels in mutant animals. In human brain, we detected similar splice variants lacking exons 28 and 29. The ability of alternatively spliced transcripts to encode different protein isoforms with individual functions in the cell, combined with the known role of splicing in disease, renders these novel transcripts of interest in the context of HD pathogenesis.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Medicine
Subjects: Q Science > QH Natural history > QH301 Biology
Q Science > QH Natural history > QH426 Genetics
Uncontrolled Keywords: Huntington's disease; RNA processing; alternative transcripts; pathogenesis; protein modelling
Publisher: Elsevier
ISSN: 0022-2836
Date of Acceptance: 25 December 2013
Last Modified: 15 Sep 2019 22:32
URI: http://orca.cf.ac.uk/id/eprint/58128

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