ZFIN ID: ZDB-PUB-091101-26
Mutation of the Bone Morphogenetic Protein GDF3 causes ocular and skeletal anomalies
Ye, M., Berry-Wynne, K.M., Asai-Coakwell, M., Sundaresan, P., Footz, T., French, C.R., Abitbol, M., Fleisch, V.C., Corbett, N., Allison, W.T., Drummond, G., Walter, M.A., Underhill, T.M., Waskiewicz, A.J., and Lehmann, O.J.
Date: 2010
Source: Human molecular genetics   19(2): 287-298 (Journal)
Registered Authors: Allison, Ted, Fleisch, Valerie, Lehmann, Ordan J., Waskiewicz, Andrew
Keywords: none
MeSH Terms:
  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Eye Abnormalities/genetics*
  • Eye Abnormalities/metabolism
  • Female
  • Growth Differentiation Factor 3/chemistry
  • Growth Differentiation Factor 3/genetics*
  • Growth Differentiation Factor 3/metabolism
  • Humans
  • Male
  • Molecular Sequence Data
  • Muscle, Skeletal/abnormalities*
  • Muscle, Skeletal/metabolism
  • Mutation*
  • Pedigree
  • Sequence Alignment
  • Transforming Growth Factor beta/genetics
  • Transforming Growth Factor beta/metabolism
  • Zebrafish/genetics
  • Zebrafish/growth & development
  • Zebrafish/metabolism
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed: 19864492 Full text @ Hum. Mol. Genet.
Ocular mal-development results in heterogeneous and frequently visually disabling phenotypes that include coloboma and microphthalmia. Due to the contribution of bone morphogenetic proteins to such processes, the function of the paralogue Growth Differentiation Factor 3 was investigated. Multiple mis-sense variants were identified in patients with ocular and/or skeletal (Klippel-Feil) anomalies including one individual with heterozygous alterations in GDF3 and GDF6. These variants were characterized, individually and in combination, through integrated biochemical and zebrafish model organism analyses, demonstrating appreciable effects with Western blot analyses, luciferase based reporter assays and antisense morpholino inhibition. Notably, inhibition of the zebrafish co-orthologue of GDF3 accurately recapitulates patient phenotypes. By demonstrating the pleiotropic effects of GDF3 mutation, these results extend the contribution of perturbed BMP signaling to human disease and potentially implicate multi-allelic inheritance of BMP variants in developmental disorders.