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X-Linked Hypophosphatemia Attributable to Pseudoexons of the PHEX Gene

Molecular Endocrinology Group (P.T.C., B.H., M.A.N., R.V.T.), Nuffield Department of Medicine, Level 7, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, United Kingdom; and Metabolic Research Unit (M.P.W.), Shriners Hospitals for Children, and Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, Missouri 63131 and 63110

Address all correspondence and requests for reprints to: Prof. R. V. Thakker M.D., F.R.C.P., F.R.C.Path., F.Med.Sci., Molecular Endocrinology Group, Nuffield Department of Medicine, Level 7, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, United Kingdom. E-mail: rajesh.thakker{at}ndm.ox.ac.uk

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.

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