Genomic Organization of the Human PEX Gene Mutated in X-Linked Dominant Hypophosphatemic Rickets
- Fiona Francis1,8,
- Tim M. Strom2,
- Steffen Hennig1,
- Annett Böddrich1,
- Bettina Lorenz2,
- Oliver Brandau2,
- Klaus L. Mohnike3,
- Michele Cagnoli3,
- Christina Steffens1,
- Sven Klages1,
- Katja Borzym1,
- Thomas Pohl4,
- Claudine Oudet5,
- Michael J. Econs6,
- Peter S.N. Rowe7,
- Richard Reinhardt1,
- Thomas Meitinger2, and
- Hans Lehrach1
- 1Max-Planck Institut für Molekulare Genetik, Berlin 14195, Germany; 2Abteilung Medizinische Genetik, Kinderpoliklinik der Ludwig-Maximilians-Universität, München 80336, Germany; 3Zentrum für Kinderheilkunde, Otto-von-Guericke Universität, Magdeburg 39112, Germany; 4Gesellschaft für Analyse-Technik und Consulting mbH (GATC), Konstanz D-78467, Germany; 5Institut de Génétique et de Biologie Moleculaire et Cellulaire (IGBMC), 67404 Illkirch, France; 6Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710; 7University College London, Department of Medicine, Middlesex Hospital, London W1N 8AA, UK
Abstract
X-linked dominant hypophosphatemic rickets (HYP) is the most common form of hereditary rickets. Recently we have cloned thePEX gene and shown it to be mutated and deleted in HYP individuals. We have now completely sequenced a 243-kb genomic region containing PEX and have identified all intron–exon boundary sequences. We show that PEX, homologous to members of a neutral endopeptidase family, has an exon organization that is very similar to neprilysin. We have performed an extensive mutation 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 deletions. 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 that most of the familial and also a large number of the sporadic cases of hypophosphatemia are caused by loss-of-function mutations in PEX.
[The sequence data described in this paper have been submitted to GenBank under accession nos.Y08111–Y08132 and Y10196.]
Footnotes
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↵8 Corresponding author.
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E-MAIL francis{at}mpimg-berlin-dahlem.mpg.de; FAX +49 30 8413 1380.
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- Received January 14, 1997.
- Accepted April 1, 1997.
- Cold Spring Harbor Laboratory Press
