Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP) |
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Authors: | Rowe PS; Oudet CL; Francis F; Sinding C; Pannetier S; Econs MJ; Strom TM; Meitinger T; Garabedian M; David A; Macher MA; Questiaux E; Popowska E; Pronicka E; Read AP; Mokrzycki A; Glorieux FH; Drezner MK; Hanauer A; Lehrach H; Goulding JN; O'Riordan JL |
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Affiliation: | Department of Medicine, University College London, Middlesex Hospital, UK. |
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Abstract: | 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.
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