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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 ?1A, 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 ?1A subunit. The second expresses a transcription factor, ?1ACT, which coordinates expression of a program of genes involved in neural and Purkinje cell development. ?1ACT also contains the polyglutamine (polyQ) tract that, when expanded, causes spinocerebellar ataxia type 6 (SCA6). When expressed as an independent polypeptide, ?1ACT-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.

SUBMITTER: Du X

PROVIDER: S-EPMC3939801 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Second cistron in CACNA1A gene encodes a transcription factor mediating cerebellar development and SCA6.

Du Xiaofei X Wang Jun J Zhu Haipeng H Rinaldo Lorenzo L Lamar Kay-Marie KM Palmenberg Ann C AC Hansel Christian C Gomez Christopher M CM

Cell 20130701 1

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 ne ...[more]

PMID: 23827678

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Project description:BACKGROUND: The genus Orbivirus includes several species that infect livestock - including Bluetongue virus (BTV) and African horse sickness virus (AHSV). These viruses have linear dsRNA genomes divided into ten segments, all of which have previously been assumed to be monocistronic. RESULTS: Bioinformatic evidence is presented for a short overlapping coding sequence (CDS) in the Orbivirus genome segment 9, overlapping the VP6 cistron in the +1 reading frame. In BTV, a 77-79 codon AUG-initiated open reading frame (hereafter ORFX) is present in all 48 segment 9 sequences analysed. The pattern of base variations across the 48-sequence alignment indicates that ORFX is subject to functional constraints at the amino acid level (even when the constraints due to coding in the overlapping VP6 reading frame are taken into account; MLOGD software). In fact the translated ORFX shows greater amino acid conservation than the overlapping region of VP6. The ORFX AUG codon has a strong Kozak context in all 48 sequences. Each has only one or two upstream AUG codons, always in the VP6 reading frame, and (with a single exception) always with weak or medium Kozak context. Thus, in BTV, ORFX may be translated via leaky scanning. A long (83-169 codon) ORF is present in a corresponding location and reading frame in all other Orbivirus species analysed except Saint Croix River virus (SCRV; the most divergent). Again, the pattern of base variations across sequence alignments indicates multiple coding in the VP6 and ORFX reading frames. CONCLUSION: At approximately 9.5 kDa, the putative ORFX product in BTV is too small to appear on most published protein gels. Nonetheless, a review of past literature reveals a number of possible detections. We hope that presentation of this bioinformatic analysis will stimulate an attempt to experimentally verify the expression and functional role of ORFX, and hence lead to a greater understanding of the molecular biology of these important pathogens.

Dataset Information

Second cistron in CACNA1A gene encodes a transcription factor mediating cerebellar development and SCA6.

Publications

Second cistron in CACNA1A gene encodes a transcription factor mediating cerebellar development and SCA6.

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