The human gephyrin (GPHN) gene: structure, chromosome localization and expression in non-neuronal cells.

Gephyrin was first described as a peripheral membrane protein of 93 kDa anchoring the glycine receptor (GlyR) to subsynaptic microtubules and cytoskeleton. Analysis of knock-out mice demonstrated that gephyrin has additional functions in GABA(A) receptor localization at the synapse and in the biosynthetic pathway of the molybdenum cofactor (Moco). Here we describe a human non-neuronal gephyrin cDNA and the exon/intron organization of the human gephyrin gene. We found the coding region to consist of 27 exons and to span approximately 800 kb on the long arm of chromosome 14. This structure is almost identical to that of the mouse gephyrin gene except that sequences corresponding to three exons described in rat and mouse could not be identified in human. Mutations of the GlyR subunits and of gephyrin lead to severe neuromotor phenotypes in human and mouse. Hyperekplexia involves most frequently a mutation in the GlyR alpha1 subunit in humans. However, inactivation of the Moco biosynthesis pathway results in very similar symptomatology. The recent characterization of a deletion of two exons of the gephyrin gene in a patient with symptoms typical of Moco deficiency confirmed that the involvement of gephyrin in these pathologies cannot be excluded. The precise localization of the gephyrin gene allowed us to exclude it from being a candidate for the autosomal dominant spastic paraplegia, the locus of which maps to 14q between markers D14S259 and D14S1018. A description of its structure and exon boundaries should lay the groundwork for further analysis of its expression in humans.