A mutation in the gene for the neurotransmitter receptor-clustering protein gephyrin causes a novel form of molybdenum cofactor deficiency

Gephyrin was originally identified as a membrane-associated protein that is essential for the postsynaptic localization of receptors for the neurotran smitters glycine and GABA,. A sequence comparison revealed homologies betwe en gephyrin and proteins necessary for the biosynthesis of the universal mo lybdenum cofactor (MoCo). Because gephyrin expression can rescue a MoCo-def icient mutation in bacteria, plants, and a murine cell line, it became clea r that gephyrin also plays a role in MoCo biosynthesis. Human MoCo deficien cy is a fatal disease resulting in severe neurological damage and death in early childhood. Most patients harbor MOCS1 mutations, which prohibit forma tion of a precursor, or carry MOCS2 mutations, which abrogate precursor con version to molybdopterin. The present report describes the identification o f a gephyrin gene (GEPH) deletion in a patient with symptoms typical of MoC o deficiency. Biochemical studies of the patient's fibroblasts demonstrate that gephyrin catalyzes the insertion of molybdenum into molybdopterin and suggest that this novel form of MoCo deficiency might be curable by molybda te supplementation.