title: Discovery of novel isoforms of huntingtin reveals a new hominid-specific exon.
abstract: Huntington's disease (HD) is a devastating neurological disorder that is caused by an expansion of the poly-Q tract in exon 1 of the Huntingtin gene (HTT). HTT is an evolutionarily conserved and ubiquitously expressed protein that has been linked to a variety of functions including transcriptional regulation, mitochondrial function, and vesicle transport. This large protein has numerous caspase and calpain cleavage sites and can be decorated with several post-translational modifications such as phosphorylations, acetylations, sumoylations, and palmitoylations. However, the exact function of HTT and the role played by its modifications in the cell are still not well understood. Scrutiny of HTT function has been focused on a single, full length mRNA. In this study, we report the discovery of 5 novel HTT mRNA splice isoforms that are expressed in normal and HTT-expanded human embryonic stem cell (hESC) lines as well as in cortical neurons differentiated from hESCs. Interestingly, none of the novel isoforms generates a truncated protein. Instead, 4 of the 5 new isoforms specifically eliminate domains and modifications to generate smaller HTT proteins. The fifth novel isoform incorporates a previously unreported additional exon, dubbed 41b, which is hominid-specific and introduces a potential phosphorylation site in the protein. The discovery of this hominid-specific isoform may shed light on human-specific pathogenic mechanisms of HTT, which could not be investigated with current mouse models of the disease.
authors.affiliation: Laboratory of Molecular Embryology, The Rockefeller University, New York, New York, United States of America.
authors.forename: Albert
authors.initials: A
authors.lastname: Ruzo
authors.affiliation: Laboratory of Molecular Embryology, The Rockefeller University, New York, New York, United States of America.
authors.forename: Ismail
authors.initials: I
authors.lastname: Ismailoglu
authors.affiliation: Laboratory of Molecular Embryology, The Rockefeller University, New York, New York, United States of America.
authors.forename: Melissa
authors.initials: M
authors.lastname: Popowski
authors.affiliation: Laboratory of Molecular Embryology, The Rockefeller University, New York, New York, United States of America.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Haremaki
authors.affiliation: Laboratory of Molecular Embryology, The Rockefeller University, New York, New York, United States of America.
authors.forename: Gist F
authors.initials: GF
authors.lastname: Croft
authors.affiliation: Laboratory of Molecular Embryology, The Rockefeller University, New York, New York, United States of America.
authors.forename: Alessia
authors.initials: A
authors.lastname: Deglincerti
authors.affiliation: Laboratory of Molecular Embryology, The Rockefeller University, New York, New York, United States of America.
authors.forename: Ali H
authors.initials: AH
authors.lastname: Brivanlou
mesh_terms: D000818:Animals; D005091:Exons; D000066449:Human Embryonic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity
chemical_list: C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger