Evidence of functional redundancy between MID proteins: implications for the presentation of Opitz syndrome.

Opitz G/BBB syndrome (OS) is a congenital defect characterized by hypertelorism and hypospadias, but additional midline malformations are also common in OS patients. X-linked OS is caused by mutations in the ubiquitin ligase MID1. In chick, MID1 is involved in left-right determination: a mutually repressive relationship between Shh and cMid1 in Hensen's node plays a key role in establishing the avian left-right axis. We have utilized our existing knowledge of the molecular basis of avian L/R determination to investigate the possible existence of functional redundancy between MID1 and its close homologue MID2. The expression of cMid2 overlaps with that of cMid1 in the node, and we demonstrate that MID2 can both mimic MID1 function as a right side determinant and rescue the laterality defects caused by knocking down endogenous MID proteins in the node. Our results show that MID2 is able to compensate for an absence in MID1 during chick left-right determination and may explain why OS patients do not suffer laterality defects despite the association between midline and L/R development. The demonstration of functional redundancy between MID1 and MID2 in the node provides supports for the hypothesis that partial functional redundancy between MID proteins in other developing structures contributes to the wide variability of OS phenotype.