X-linked hypophosphatemia attributable to pseudoexons of the PHEX gene

X-linked hypophosphatemia is commonly caused by mutations of the coding reg ion of PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). However, such PHEX mutations are not detected in approx imately one third of X-linked hypophosphatemia patients who may harbor defe cts in the noncoding or intronic regions. We have therefore investigated 11 unrelated X-linked hypophosphatemia patients in whom coding region mutatio ns 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 lea d to missense peptides and premature termination codons. The origin of thes e 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 (ggaa gg to gtaagg). Splicing between this novel donor splice site and 3 preexist ing, 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.