title: X-linked hypophosphatemia attributable to pseudoexons of the PHEX gene.
abstract: X-linked hypophosphatemia is commonly caused by mutations of the coding region of PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). However, such PHEX mutations are not detected in approximately one third of X-linked hypophosphatemia patients who may harbor defects in the noncoding or intronic regions. We have therefore investigated 11 unrelated X-linked hypophosphatemia patients in whom coding region mutations had been excluded, for intronic mutations that may lead to mRNA splicing abnormalities, by the use of lymphoblastoid RNA and RT-PCRs. One X-linked hypophosphatemia patient was found to have 3 abnormally large transcripts, resulting from 51-bp, 100-bp, and 170-bp insertions, all of which would lead to missense peptides and premature termination codons. The origin of these transcripts was a mutation (g to t) at position +1268 of intron 7, which resulted in the occurrence of a high quality novel donor splice site (ggaagg to gtaagg). Splicing between this novel donor splice site and 3 preexisting, but normally silent, acceptor splice sites within intron 7 resulted in the occurrences of the 3 pseudoexons. This represents the first report of PHEX pseudoexons and reveals further the diversity of genetic abnormalities causing X-linked hypophosphatemia.
authors.affiliation: Molecular Endocrinology, Nuffield Department of Medicine, Level 7, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, United Kingdom.
authors.forename: P T
authors.initials: PT
authors.lastname: Christie
authors.forename: B
authors.initials: B
authors.lastname: Harding
authors.forename: M A
authors.initials: MA
authors.lastname: Nesbit
authors.forename: M P
authors.initials: MP
authors.lastname: Whyte
authors.forename: R V
authors.initials: RV
authors.lastname: Thakker
mesh_terms: D002478:Cells, Cultured; D004251:DNA Transposable Elements; D005091:Exons; D005260:Female; D006801:Humans; D007015:Hypophosphatemia, Familial / Q000097:blood / Q000235:genetics*; D007438:Introns; D008214:Lymphocytes / Q000502:physiology; D008297:Male; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; D010375:Pedigree; D011506:Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
chemical_list: D004251:DNA Transposable Elements; D011506:Proteins; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506231:PHEX protein, human