GENOMIC ORGANIZATION OF THE HUMAN PEX GENE MUTATED IN X-LINKED DOMINANT HYPOPHOSPHATEMIC RICKETS

X-linked dominant hypophosphatemic rickets (HYP) is the most common fo rm of hereditary rickets. Recently we have cloned the PEX gene and sho wn it to be mutated and deleted in HYP individuals. We have now comple tely sequenced a 243-kb genomic region containing PEX and have identif ied all intron-exon boundary sequences. We show that PEX, homologous t o members of a neutral endopeptidase family, has an exon organization that is very similar to neprilysin. We have performed an extensive mut ation analysis examining all 22 PEX coding exons in 29 familial and 14 sporadic cases of hypophosphatemia. Sequence changes include missense , frameshift, nonsense, and splice site mutations and intragenic delet ions. A mutation was found in 25 (86%) of the 29 familial cases and 8 (57%) of the 14 sporadic cases. Our data provide the first evidence th at most of the familial and also a large number of the sporadic cases of hypophosphatemia are caused by loss-of-function mutations in PEX.