Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP)

Mutations in the PEX gene at Xp22.1 (phosphate-regulating gene withhomologies to endopeptidases, on the X-chromosome), are responsible forX-linked hypophosphataemic rickets (HYP). Homology of PEX to the M13 familyof Zn2+ metallopeptidases which include neprilysin (NEP) as prototype, hasraised important questions regarding PEX function at the molecular level.The aim of this study was to analyse 99 HYP families for PEX genemutations, and to correlate predicted changes in the protein structure withZn2+ metallopeptidase gene function. Primers flanking 22 characterisedexons were used to amplify DNA by PCR, and SSCP was then used to screen formutations. Deletions, insertions, nonsense mutations, stop codons andsplice mutations occurred in 83% of families screened for in all 22 exons,and 51% of a separate set of families screened in 17 PEX gene exons.Missense mutations in four regions of the gene were informative regardingfunction, with one mutation in the Zn2+-binding site predicted to altersubstrate enzyme interaction and catalysis. Computer analysis of theremaining mutations predicted changes in secondary structure,N-glycosylation, protein phosphorylation and catalytic site molecularstructure. The wide range of mutations that align with regions required forprotease activity in NEP suggests that PEX also functions as a protease,and may act by processing factor(s) involved in bone mineral metabolism.