title: GDF6, a novel locus for a spectrum of ocular developmental anomalies.
abstract: Colobomata represent visually impairing ocular closure defects that are associated with a diverse range of developmental anomalies. Characterization of a chromosome 8q21.2-q22.1 segmental deletion in a patient with chorioretinal coloboma revealed elements of nonallelic homologous recombination and nonhomologous end joining. This genomic architecture extends the range of chromosomal rearrangements associated with human disease and indicates that a broader spectrum of human chromosomal rearrangements may use coupled homologous and nonhomologous mechanisms. We also demonstrate that the segmental deletion encompasses GDF6, encoding a member of the bone-morphogenetic protein family, and that inhibition of gdf6a in a model organism accurately recapitulates the proband's phenotype. The spectrum of disorders generated by morpholino inhibition and the more severe defects (microphthalmia and anophthalmia) observed at higher doses illustrate the key role of GDF6 in ocular development. These results underscore the value of integrated clinical and molecular investigation of patients with chromosomal anomalies.
authors.affiliation: Department of Ophthalmology and Medical Genetics, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada.
authors.forename: Mika
authors.initials: M
authors.lastname: Asai-Coakwell
authors.forename: Curtis R
authors.initials: CR
authors.lastname: French
authors.forename: Karyn M
authors.initials: KM
authors.lastname: Berry
authors.forename: Ming
authors.initials: M
authors.lastname: Ye
authors.forename: Ron
authors.initials: R
authors.lastname: Koss
authors.forename: Martin
authors.initials: M
authors.lastname: Somerville
authors.forename: Rosemary
authors.initials: R
authors.lastname: Mueller
authors.forename: Veronica
authors.initials: V
authors.lastname: van Heyningen
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Waskiewicz
authors.forename: Ordan J
authors.initials: OJ
authors.lastname: Lehmann
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics* / Q000378:metabolism; D002869:Chromosome Aberrations; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D003103:Coloboma / Q000235:genetics*; D004195:Disease Models, Animal; D004625:Embryo, Nonmammalian / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D055431:Growth Differentiation Factor 6; D006801:Humans; D007621:Karyotyping; D008297:Male; D010641:Phenotype; D011995:Recombination, Genetic; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; C525906:GDF6 protein, human; D055431:Growth Differentiation Factor 6; D029961:Zebrafish Proteins; C420987:gdf6a protein, zebrafish