Copyright © 2006 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 80, Issue 2, 306-315, 1 February 2007
doi:10.1086/511280
Article
GDF6, a Novel Locus for a Spectrum of Ocular Developmental Anomalies
Mika Asai-Coakwell*, a, c, Curtis R. French*, b, Karyn M. Berryb, Ming Yea, c, Ron Kossb, Martin Somervillec, Rosemary Muellerc, Veronica van Heyningend, Andrew J. Waskiewiczb and Ordan J. Lehmanna, c, 
, 
a From the Departments of Ophthalmology, Edinburgh
b Biological Sciences, Edinburgh
c and Medical Genetics, Edinburgh
d University of Alberta, Edmonton; and Medical Research Council Human Genetics Unit, Edinburgh
Address for correspondence and reprints: Dr. Ordan J. Lehmann, Departments of Ophthalmology and Medical Genetics, 8–29 Medical Sciences Building, University of Alberta, Edmonton, Alberta, Canada T6G 2H7* These two authors contributed equally to this work.
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.
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