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

Peter S.N. Rowe, Claudine L. Oudet, Fiona Francis, Christiane Sinding, Solange Pannetier, Mike J. Econs, Tim M. Strom, Thomas Meitinger, Michele Garabedian, Albert David, Marie Alice Macher, Elisabeth Questiaux, Ewa Popowska, Ewa Pronicka, Andrew P. Read, Agnes Mokrzycki, Francis H. Glorieux, Marc K. Drezner, Andre Hanauer, Hans LehrachJohnathan N. Goulding, Jeffrey L.H. O'Riordan

Research output: Contribution to journalArticlepeer-review

152 Scopus citations


Mutations in the PEX gene at Xp22.1 (phosphate-regulating gene with homologies to endopeptidases, on the X-chromosome), are responsible for X-linked hypophosphataemic rickets (HYP). Homology of PEX to the M13 family of Zn2+ metallopeptidases which include neprilysin (NEP) as prototype, has raised important questions regarding PEX function at the molecular level. The aim of this study was to analyse 99 HYP families for PEX gene mutations, and to correlate predicted changes in the protein structure with Zn2+ metallopeptidase gene function. Primers flanking 22 characterised exons were used to amplify DNA by PCR, and SSCP was then used to screen for mutations. Deletions, insertions, nonsense mutations, stop codons and splice 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 regarding function, with one mutation in the Zn2+-binding site predicted to alter substrate-enzyme interaction and catalysis. Computer analysis of the remaining mutations predicted changes in secondary structure, N-glycosylation, protein phosphorylation and catalytic site molecular structure. The wide range of mutations that align with regions required for protease activity in NEP suggests that PEX also functions as a protease, and may act by processing factor(s) involved in bone mineral metabolism.

Original languageEnglish (US)
Pages (from-to)539-549
Number of pages11
JournalHuman molecular genetics
Issue number4
StatePublished - Apr 1997

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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