Molecular modelling of the norrie disease protein predicts a cystine knot growth factor tertiary structure

The X–lined gene for Norrie disease, which is characterized by blindness, deafness and mental retardation has been cloned recently. This gene has been thought to code for a putative extracellular factor; its predicted amino acid sequence is homologous to the C–terminal domain of diverse extracellular proteins. Sequence pattern searches and three–dimensional modelling now suggest that the Norrie disease protein (NDP) has a tertiary structure similar to that of transforming growth factor ß (TGFß). Our model identifies NDP as a member of an emerging family of growth factors containing a cystine knot motif, with direct implications for the physiological role of NDP. The model also sheds light on sequence related domains such as the C–terminal domain of mucins and of von Willebrand factor.