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.
Citation
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. (2009) Incomplete penetrance and phenotypic variability characterize Gdf6-attributable oculo-skeletal phenotypes. Human molecular genetics. 18(6):1110-1121.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping