title: Second cistron in CACNA1A gene encodes a transcription factor mediating cerebellar development and SCA6.
abstract: The CACNA1A gene, encoding the voltage-gated calcium channel subunit α1A, is involved in pre- and postsynaptic Ca(2+) signaling, gene expression, and several genetic neurological disorders. We found that CACNA1A coordinates gene expression using a bicistronic mRNA bearing a cryptic internal ribosomal entry site (IRES). The first cistron encodes the well-characterized α1A subunit. The second expresses a transcription factor, α1ACT, which coordinates expression of a program of genes involved in neural and Purkinje cell development. α1ACT also contains the polyglutamine (polyQ) tract that, when expanded, causes spinocerebellar ataxia type 6 (SCA6). When expressed as an independent polypeptide, α1ACT-bearing an expanded polyQ tract-lacks transcription factor function and neurite outgrowth properties, causes cell death in culture, and leads to ataxia and cerebellar atrophy in transgenic mice. Suppression of CACNA1A IRES function in SCA6 may be a potential therapeutic strategy.
authors.affiliation: Department of Neurology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Du
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Haipeng
authors.initials: H
authors.lastname: Zhu
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Rinaldo
authors.forename: Kay-Marie
authors.initials: KM
authors.lastname: Lamar
authors.forename: Ann C
authors.initials: AC
authors.lastname: Palmenberg
authors.forename: Christian
authors.initials: C
authors.lastname: Hansel
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Gomez
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000235:genetics* / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D002531:Cerebellum / Q000196:embryology / Q000503:physiopathology; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D016501:Neurites / Q000378:metabolism; D010455:Peptides / Q000235:genetics; D011689:Purkinje Cells / Q000378:metabolism; D051381:Rats; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D020864:Calcium Channels, N-Type
chemical_list: D015220:Calcium Channels; D010455:Peptides; D014157:Transcription Factors; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type; C097188:polyglutamine