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, Michael 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 Lehrach & 2 others Johnathan N. Goulding, Jeffrey L H O'Riordan

Research output: Contribution to journalArticle

148 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)539-549
Number of pages11
JournalHuman Molecular Genetics
Volume6
Issue number4
DOIs
StatePublished - Apr 1997
Externally publishedYes

Fingerprint

Familial Hypophosphatemic Rickets
Mutation
Genes
Neprilysin
Exons
Metalloproteases
Peptide Hydrolases
Hypophosphatemic Rickets
Single-Stranded Conformational Polymorphism
Endopeptidases
Terminator Codon
Nonsense Codon
Insertional Mutagenesis
X Chromosome
Missense Mutation
Molecular Structure
Catalysis
Glycosylation
Minerals
Catalytic Domain

ASJC Scopus subject areas

  • Genetics

Cite this

Rowe, P. S. N., Oudet, C. L., Francis, F., Sinding, C., Pannetier, S., Econs, M., ... O'Riordan, J. L. H. (1997). Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP). Human Molecular Genetics, 6(4), 539-549. https://doi.org/10.1093/hmg/6.4.539

Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP). / Rowe, Peter S N; Oudet, Claudine L.; Francis, Fiona; Sinding, Christiane; Pannetier, Solange; Econs, Michael; Strom, Tim M.; Meitinger, Thomas; Garabedian, Michele; David, Albert; Macher, Marie Alice; Questiaux, Elisabeth; Popowska, Ewa; Pronicka, Ewa; Read, Andrew P.; Mokrzycki, Agnes; Glorieux, Francis H.; Drezner, Marc K.; Hanauer, Andre; Lehrach, Hans; Goulding, Johnathan N.; O'Riordan, Jeffrey L H.

In: Human Molecular Genetics, Vol. 6, No. 4, 04.1997, p. 539-549.

Research output: Contribution to journalArticle

Rowe, PSN, Oudet, CL, Francis, F, Sinding, C, Pannetier, S, Econs, M, 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, JLH 1997, 'Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP)', Human Molecular Genetics, vol. 6, no. 4, pp. 539-549. https://doi.org/10.1093/hmg/6.4.539
Rowe, Peter S N ; Oudet, Claudine L. ; Francis, Fiona ; Sinding, Christiane ; Pannetier, Solange ; Econs, Michael ; Strom, Tim M. ; Meitinger, Thomas ; Garabedian, Michele ; David, Albert ; Macher, Marie Alice ; Questiaux, Elisabeth ; Popowska, Ewa ; Pronicka, Ewa ; Read, Andrew P. ; Mokrzycki, Agnes ; Glorieux, Francis H. ; Drezner, Marc K. ; Hanauer, Andre ; Lehrach, Hans ; Goulding, Johnathan N. ; O'Riordan, Jeffrey L H. / Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP). In: Human Molecular Genetics. 1997 ; Vol. 6, No. 4. pp. 539-549.
@article{68b3f7bfba7148cb8cf43edcc982531e,
title = "Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP)",
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.",
author = "Rowe, {Peter S N} and Oudet, {Claudine L.} and Fiona Francis and Christiane Sinding and Solange Pannetier and Michael Econs and Strom, {Tim M.} and Thomas Meitinger and Michele Garabedian and Albert David and Macher, {Marie Alice} and Elisabeth Questiaux and Ewa Popowska and Ewa Pronicka and Read, {Andrew P.} and Agnes Mokrzycki and Glorieux, {Francis H.} and Drezner, {Marc K.} and Andre Hanauer and Hans Lehrach and Goulding, {Johnathan N.} and O'Riordan, {Jeffrey L H}",
year = "1997",
month = "4",
doi = "10.1093/hmg/6.4.539",
language = "English (US)",
volume = "6",
pages = "539--549",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "4",

}

TY - JOUR

T1 - Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP)

AU - Rowe, Peter S N

AU - Oudet, Claudine L.

AU - Francis, Fiona

AU - Sinding, Christiane

AU - Pannetier, Solange

AU - Econs, Michael

AU - Strom, Tim M.

AU - Meitinger, Thomas

AU - Garabedian, Michele

AU - David, Albert

AU - Macher, Marie Alice

AU - Questiaux, Elisabeth

AU - Popowska, Ewa

AU - Pronicka, Ewa

AU - Read, Andrew P.

AU - Mokrzycki, Agnes

AU - Glorieux, Francis H.

AU - Drezner, Marc K.

AU - Hanauer, Andre

AU - Lehrach, Hans

AU - Goulding, Johnathan N.

AU - O'Riordan, Jeffrey L H

PY - 1997/4

Y1 - 1997/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=8244251430&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=8244251430&partnerID=8YFLogxK

U2 - 10.1093/hmg/6.4.539

DO - 10.1093/hmg/6.4.539

M3 - Article

VL - 6

SP - 539

EP - 549

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 4

ER -