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

Am J Hum Genet. 2001 Jan;68(1):208-13. doi: 10.1086/316941. Epub 2000 Nov 28.


Gephyrin was originally identified as a membrane-associated protein that is essential for the postsynaptic localization of receptors for the neurotransmitters glycine and GABA(A). A sequence comparison revealed homologies between gephyrin and proteins necessary for the biosynthesis of the universal molybdenum cofactor (MoCo). Because gephyrin expression can rescue a MoCo-deficient mutation in bacteria, plants, and a murine cell line, it became clear that gephyrin also plays a role in MoCo biosynthesis. Human MoCo deficiency is a fatal disease resulting in severe neurological damage and death in early childhood. Most patients harbor MOCS1 mutations, which prohibit formation of a precursor, or carry MOCS2 mutations, which abrogate precursor conversion to molybdopterin. The present report describes the identification of a gephyrin gene (GEPH) deletion in a patient with symptoms typical of MoCo 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 molybdate supplementation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Carbon-Carbon Lyases
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism*
  • Coenzymes / chemistry
  • Coenzymes / deficiency*
  • Coenzymes / metabolism
  • Coenzymes / therapeutic use
  • DNA Mutational Analysis
  • Exons / genetics
  • Fibroblasts
  • Gene Deletion
  • Humans
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism*
  • Metalloproteins / chemistry
  • Metalloproteins / metabolism
  • Molecular Sequence Data
  • Molybdenum / chemistry
  • Molybdenum / deficiency*
  • Molybdenum / metabolism
  • Molybdenum / therapeutic use
  • Molybdenum Cofactors
  • Mutation / genetics*
  • Nuclear Proteins / genetics
  • Pteridines / chemistry
  • Pteridines / metabolism
  • Receptor Aggregation
  • Receptors, Neurotransmitter / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sulfurtransferases / genetics


  • Carrier Proteins
  • Coenzymes
  • Membrane Proteins
  • Metalloproteins
  • Molybdenum Cofactors
  • Nuclear Proteins
  • Pteridines
  • Receptors, Neurotransmitter
  • gephyrin
  • Molybdenum
  • molybdenum cofactor
  • Sulfurtransferases
  • molybdopterin synthase
  • Carbon-Carbon Lyases
  • MOCS1 protein, human

Associated data

  • GENBANK/AB272663
  • GENBANK/AF102544
  • GENBANK/X66366