Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP)
| Autor: | J. L. H. O'Riordan, Tim M. Strom, C. Oudet, Thomas Meitinger, Solange Pannetier, Johnathan N. Goulding, Christiane Sinding, Marc K. Drezner, Ewa Popowska, Ewa Pronicka, Peter S. N. Rowe, André Hanauer, Marie Alice Macher, Michèle Garabédian, Albert David, Andrew P. Read, Elisabeth Questiaux, Francis H. Glorieux, Agnes Mokrzycki, Hans Lehrach, Mike J. Econs, Fiona Francis |
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| Rok vydání: | 1997 |
| Předmět: |
DNA
Complementary Databases Factual RNA Splicing Molecular Sequence Data Nonsense mutation Gene mutation Biology Polymerase Chain Reaction Exon Metallopeptidase Gene Genetics Humans Amino Acid Sequence Cloning Molecular Molecular Biology Gene Hypophosphatemia Familial Polymorphism Single-Stranded Conformational Genetics (clinical) DNA Primers Sequence Deletion Binding Sites Base Sequence Sequence Homology Amino Acid PHEX Nucleic acid sequence Metalloendopeptidases Proteins General Medicine PHEX Phosphate Regulating Neutral Endopeptidase Stop codon Mutation Codon Terminator |
| Zdroj: | Human Molecular Genetics. 6:539-549 |
| ISSN: | 1460-2083 |
| Popis: | 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 Zn 2+ 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 Zn 2+ 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 Zn 2+ -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. |
| Databáze: | OpenAIRE |
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