Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal anomalies.
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.
Department of Ophthalmology, University of Alberta, Edmonton, Canada.
Ming
M
Ye
Karyn M
KM
Berry-Wynne
Mika
M
Asai-Coakwell
Periasamy
P
Sundaresan
Tim
T
Footz
Curtis R
CR
French
Marc
M
Abitbol
Valerie C
VC
Fleisch
Nathan
N
Corbett
W Ted
WT
Allison
Garry
G
Drummond
Michael A
MA
Walter
T Michael
TM
Underhill
Andrew J
AJ
Waskiewicz
Ordan J
OJ
Lehmann
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D005124:Eye Abnormalities / Q000235:genetics* / Q000378:metabolism; D005260:Female; D055451:Growth Differentiation Factor 3 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000002:abnormalities* / Q000378:metabolism; D009154:Mutation; D010375:Pedigree; D016415:Sequence Alignment; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
C079678:Gdf3 protein, zebrafish; D055451:Growth Differentiation Factor 3; D016212:Transforming Growth Factor beta; D029961:Zebrafish Proteins