title: Ahsa1 and Hsp90 activity confers more severe craniofacial phenotypes in a zebrafish model of hypoparathyroidism, sensorineural deafness and renal dysplasia (HDR).
abstract: The severity of most human birth defects is highly variable. Our ability to diagnose, treat and prevent defects relies on our understanding of this variability. Mutation of the transcription factor GATA3 in humans causes the highly variable hypoparathyroidism, sensorineural deafness and renal dysplasia (HDR) syndrome. Although named for a triad of defects, individuals with HDR can also exhibit craniofacial defects. Through a forward genetic screen for craniofacial mutants, we isolated a zebrafish mutant in which the first cysteine of the second zinc finger of Gata3 is mutated. Because mutation of the homologous cysteine causes HDR in humans, these zebrafish mutants could be a quick and effective animal model for understanding the role of gata3 in the HDR disease spectrum. We demonstrate that, unexpectedly, the chaperone proteins Ahsa1 and Hsp90 promote severe craniofacial phenotypes in our zebrafish model of HDR syndrome. The strengths of the zebrafish system, including rapid development, genetic tractability and live imaging, make this an important model for variability.
authors.affiliation: Department of Molecular and Cell and Developmental Biology, Institute for Cellular and Molecular Biology, Patterson 522, University of Texas at Austin, Austin, TX 78713, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Sheehan-Rooney
authors.forename: Mary E
authors.initials: ME
authors.lastname: Swartz
authors.forename: Feng
authors.initials: F
authors.lastname: Zhao
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.forename: Johann K
authors.initials: JK
authors.lastname: Eberhart
mesh_terms: D000818:Animals; D019465:Craniofacial Abnormalities / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006319:Hearing Loss, Sensorineural / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007011:Hypoparathyroidism / Q000378:metabolism* / Q000473:pathology*; D007267:Injections; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors / Q000378:metabolism*; D060172:Morpholinos / Q000008:administration & dosage / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D009401:Nephrosis / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D015027:Zebrafish / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D050990:GATA3 Transcription Factor; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D060172:Morpholinos; D029961:Zebrafish Proteins; C587915:ahsa1a protein, zebrafish; C494747:gata3 protein, zebrafish