MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation

The gene MID1, the mutation of which causes X-linked Opitz G/BBB syndrome ( OS, MIM 300000), encodes a microtubule-associated protein (MAP). We show th at mutation of MID1 leads to a marked accumulation of the catalytic subunit of protein phosphatase 2A (PP2Ac), a central cellular regulator. PP2Ac acc umulation is caused by an impairment of a newly identified E3 ubiquitin lig ase activity of the MID1 protein that normally targets PP2Ac for degradatio n through binding to its alpha4 regulatory subunit in an embryonic fibrobla st line derived from a fetus with OS. Elevated PP2Ac causes hypophosphoryla tion of MAPs, a pathological mechanism that is consistent with the OS pheno type.