PUBLICATION

Incomplete penetrance and phenotypic variability characterize Gdf6-attributable oculo-skeletal phenotypes

Authors
Asai-Coakwell, M., French, C.R., Ye, M., Garcha, K., Bigot, K., Perera, A.G., Staehling-Hampton, K., Mema, S.C., Chanda, B., Mushegian, A., Bamforth, S., Doschak, M.R., Li, G., Dobbs, M.B., Giampietro, P.F., Brooks, B.P., Vijayalakshmi, P., Sauvé, Y., Abitbol, M., Sundaresan, P., Heyningen, V.V., Pourquié, O., Underhill, T.M., Waskiewicz, A.J., and Lehmann, O.J.
ID
ZDB-PUB-090112-12
Date
2009
Source
Human molecular genetics   18(6): 1110-1121 (Journal)
Registered Authors
Lehmann, Ordan J., Waskiewicz, Andrew
Keywords
none
MeSH Terms
  • Abnormalities, Multiple/genetics*
  • Abnormalities, Multiple/pathology*
  • Amino Acid Sequence
  • Animals
  • DNA Mutational Analysis
  • Genes, Reporter
  • Growth Differentiation Factor 6/chemistry
  • Growth Differentiation Factor 6/genetics*
  • Humans
  • Mice
  • Models, Animal
  • Molecular Sequence Data
  • Mutant Proteins/chemistry
  • Mutant Proteins/genetics
  • Mutation/genetics
  • Oligonucleotides, Antisense/pharmacology
  • Penetrance*
  • Zebrafish
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/genetics
PubMed
19129173 Full text @ Hum. Mol. Genet.
Abstract
Proteins of the bone morphogenetic protein (BMP) family are known to have a role in ocular and skeletal development; however, due to 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.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping