Incomplete penetrance and phenotypic variability characterize Gdf6-attributable oculo-skeletal phenotypes.
Proteins of the bone morphogenetic protein (BMP) family are known to have a role in ocular and skeletal development; however, because of 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.
Asai-Coakwell
Mika
M
Department of Ophthalmology, University of Alberta, Edmonton, Canada.
French
Curtis R
CR
Ye
Ming
M
Garcha
Kamal
K
Bigot
Karin
K
Perera
Anoja G
AG
Staehling-Hampton
Karen
K
Mema
Silvina C
SC
Chanda
Bhaskar
B
Mushegian
Arcady
A
Bamforth
Steven
S
Doschak
Michael R
MR
Li
Guang
G
Dobbs
Matthew B
MB
Giampietro
Philip F
PF
Brooks
Brian P
BP
Vijayalakshmi
Perumalsamy
P
Sauvé
Yves
Y
Abitbol
Marc
M
Sundaresan
Periasamy
P
van Heyningen
Veronica
V
Pourquié
Olivier
O
Underhill
T Michael
TM
Waskiewicz
Andrew J
AJ
Lehmann
Ordan J
OJ
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology*; D000595:Amino Acid Sequence; D000818:Animals; D004252:DNA Mutational Analysis; D017930:Genes, Reporter; D055431:Growth Differentiation Factor 6 / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D051379:Mice; D023421:Models, Animal; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics; D009154:Mutation / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D019683:Penetrance; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000737:chemistry / Q000235:genetics
C525906:GDF6 protein, human; C525907:Gdf6 protein, mouse; D055431:Growth Differentiation Factor 6; D050505:Mutant Proteins; D016376:Oligonucleotides, Antisense; D029961:Zebrafish Proteins; C420987:gdf6a protein, zebrafish