title: Incomplete penetrance and phenotypic variability characterize Gdf6-attributable oculo-skeletal phenotypes.
abstract: Proteins of the bone morphogenetic protein (BMP) family are known to have a role in ocular and skeletal development; however, because of their widespread expression and functional redundancy, less progress has been made identifying the roles of individual BMPs in human disease. We identified seven heterozygous mutations in growth differentiation factor 6 (GDF6), a member of the BMP family, in patients with both ocular and vertebral anomalies, characterized their effects with a SOX9-reporter assay and western analysis, and demonstrated comparable phenotypes in model organisms with reduced Gdf6 function. We observed a spectrum of ocular and skeletal anomalies in morphant zebrafish, the latter encompassing defective tail formation and altered expression of somite markers noggin1 and noggin2. Gdf6(+/-) mice exhibited variable ocular phenotypes compatible with phenotypes observed in patients and zebrafish. Key differences evident between patients and animal models included pleiotropic effects, variable expressivity and incomplete penetrance. These data establish the important role of this determinant in ocular and vertebral development, demonstrate the complex genetic inheritance of these phenotypes, and further understanding of BMP function and its contributions to human disease.
authors.affiliation: Department of Ophthalmology, University of Alberta, Edmonton, Canada.
authors.forename: Mika
authors.initials: M
authors.lastname: Asai-Coakwell
authors.forename: Curtis R
authors.initials: CR
authors.lastname: French
authors.forename: Ming
authors.initials: M
authors.lastname: Ye
authors.forename: Kamal
authors.initials: K
authors.lastname: Garcha
authors.forename: Karin
authors.initials: K
authors.lastname: Bigot
authors.forename: Anoja G
authors.initials: AG
authors.lastname: Perera
authors.forename: Karen
authors.initials: K
authors.lastname: Staehling-Hampton
authors.forename: Silvina C
authors.initials: SC
authors.lastname: Mema
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Chanda
authors.forename: Arcady
authors.initials: A
authors.lastname: Mushegian
authors.forename: Steven
authors.initials: S
authors.lastname: Bamforth
authors.forename: Michael R
authors.initials: MR
authors.lastname: Doschak
authors.forename: Guang
authors.initials: G
authors.lastname: Li
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Dobbs
authors.forename: Philip F
authors.initials: PF
authors.lastname: Giampietro
authors.forename: Brian P
authors.initials: BP
authors.lastname: Brooks
authors.forename: Perumalsamy
authors.initials: P
authors.lastname: Vijayalakshmi
authors.forename: Yves
authors.initials: Y
authors.lastname: Sauvé
authors.forename: Marc
authors.initials: M
authors.lastname: Abitbol
authors.forename: Periasamy
authors.initials: P
authors.lastname: Sundaresan
authors.forename: Veronica
authors.initials: V
authors.lastname: van Heyningen
authors.forename: Olivier
authors.initials: O
authors.lastname: Pourquié
authors.forename: T Michael
authors.initials: TM
authors.lastname: Underhill
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Waskiewicz
authors.forename: Ordan J
authors.initials: OJ
authors.lastname: Lehmann
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology*; D000595:Amino Acid Sequence; D000818:Animals; D004252:DNA Mutational Analysis; D017930:Genes, Reporter; D055431:Growth Differentiation Factor 6 / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D051379:Mice; D023421:Models, Animal; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics; D009154:Mutation / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D019683:Penetrance; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000737:chemistry / Q000235:genetics
chemical_list: C525906:GDF6 protein, human; C525907:Gdf6 protein, mouse; D055431:Growth Differentiation Factor 6; D050505:Mutant Proteins; D016376:Oligonucleotides, Antisense; D029961:Zebrafish Proteins; C420987:gdf6a protein, zebrafish