title: A murine Zic3 transcript with a premature termination codon evades nonsense-mediated decay during axis formation.
abstract: The ZIC transcription factors are key mediators of embryonic development and ZIC3 is the gene most commonly associated with situs defects (heterotaxy) in humans. Half of patient ZIC3 mutations introduce a premature termination codon (PTC). In vivo, PTC-containing transcripts might be targeted for nonsense-mediated decay (NMD). NMD efficiency is known to vary greatly between transcripts, tissues and individuals and it is possible that differences in survival of PTC-containing transcripts partially explain the striking phenotypic variability that characterizes ZIC3-associated congenital defects. For example, the PTC-containing transcripts might encode a C-terminally truncated protein that retains partial function or that dominantly interferes with other ZIC family members. Here we describe the katun (Ka) mouse mutant, which harbours a mutation in the Zic3 gene that results in a PTC. At the time of axis formation there is no discernible decrease in this PTC-containing transcript in vivo, indicating that the mammalian Zic3 transcript is relatively insensitive to NMD, prompting the need to re-examine the molecular function of the truncated proteins predicted from human studies and to determine whether the N-terminal portion of ZIC3 possesses dominant-negative capabilities. A combination of in vitro studies and analysis of the Ka phenotype indicate that it is a null allele of Zic3 and that the N-terminal portion of ZIC3 does not encode a dominant-negative molecule. Heterotaxy in patients with PTC-containing ZIC3 transcripts probably arises due to loss of ZIC3 function alone.
authors.affiliation: Early Mammalian Development Laboratory, Research School of Biology, The Australian National University, Canberra, ACT 0200, Australia.
authors.forename: Jehangir N
authors.initials: JN
authors.lastname: Ahmed
authors.forename: Radiya G
authors.initials: RG
authors.lastname: Ali
authors.forename: Nicholas
authors.initials: N
authors.lastname: Warr
authors.forename: Heather M
authors.initials: HM
authors.lastname: Wilson
authors.forename: Helen M
authors.initials: HM
authors.lastname: Bellchambers
authors.forename: Kristen S
authors.initials: KS
authors.lastname: Barratt
authors.forename: Amelia J
authors.initials: AJ
authors.lastname: Thompson
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Arkell
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism; D018389:Codon, Nonsense / Q000235:genetics*; D004058:Diffusion; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D004707:Endoderm / Q000002:abnormalities / Q000196:embryology; D054262:Gastrulation / Q000235:genetics; D059446:Heterotaxy Syndrome / Q000196:embryology* / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008648:Mesoderm / Q000002:abnormalities / Q000196:embryology; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D059365:Nonsense Mediated mRNA Decay / Q000235:genetics*; D038081:Organogenesis / Q000235:genetics; D055550:Protein Stability; D022821:RNA Splice Sites / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D051176:beta Catenin / Q000378:metabolism
chemical_list: D018389:Codon, Nonsense; D018398:Homeodomain Proteins; D050505:Mutant Proteins; D022821:RNA Splice Sites; D012333:RNA, Messenger; D014157:Transcription Factors; C491594:Zic3 protein, mouse; D051176:beta Catenin