Distribution of Mutations in the PEX Gene in Families with X-linked Hypophosphataemic Rickets (HYP)

• Published in: Human molecular genetics Vol. 6; no. 4; pp. 539 - 549
• Main Authors: Rowe, Peter S. N., Oudet, Claudine L., Francis, Fiona, Sinding, Christiane, Pannetier, Solange, Econs, Mike J., 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.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-04-1997
• Subjects: Amino Acid Sequence; Base Sequence; Binding Sites; Biological and medical sciences; Cloning, Molecular; Codon, Terminator; Databases, Factual; DNA Primers; DNA, Complementary - chemistry; Errors of metabolism; Humans; Hypophosphatemia, Familial - genetics; Medical sciences; Metabolic diseases; Metalloendopeptidases - chemistry; Metalloendopeptidases - genetics; Miscellaneous hereditary metabolic disorders; Molecular Sequence Data; Mutation; PHEX Phosphate Regulating Neutral Endopeptidase; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Proteins - chemistry; Proteins - genetics; Proteins - metabolism; RNA Splicing; Sequence Deletion; Sequence Homology, Amino Acid; Sex linked character; Molecular structure; Diseases of the osteoarticular system; Tubulopathy; Homology; Metalloendopeptidases; Bone disease; Hypophosphatemic rickets; Structure function relationship; Enzymatic activity; Gene; Vitamin D; Genetics; Catalytic site; Kidney disease; Human; Urinary system disease; Nucleotide sequence; Enzyme; Metabolic diseases; Genetic disease; Peptidases; Complementary DNA; Vitamin resistant rickets; Hydrolases; Mutation
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/6.4.539

Mutations in the PEXgene at Xp22.1 (phosphate-regulating gene with homologies to endopeptidases, on the X-chromosome), are responsible for X-linked hypo-phosphataemic 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 PEXgene mutations, and to correlate predicted changes in the protein structure with Zn2+ metallo-peptidase 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 PEXgene exons. Missense mutations in four regions of the gene were informative regarding function, with one mutation in the Zn2+-bind-ing 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.