title: PHEX analysis in 118 pedigrees reveals new genetic clues in hypophosphatemic rickets.
abstract: Familial hypophosphatemic rickets is a rare disease, which is mostly transmitted as an X-linked dominant trait, and mutations on the phosphate regulating gene with homologies to endopeptidases on the X-chromosome (PHEX) gene are responsible for the disease in most familial cases. In this study we analyzed PHEX in a large cohort of 118 pedigrees representing 56 familial cases and 62 sporadic cases. The high-resolution melting curves technique was tested as a screening method, along with classical sequencing. PHEX mutations have been found in 87% of familial cases but also in 72% of sporadic cases. Missense mutations were found in 16 probands, two of which being associated with other PHEX mutations resulting into truncated proteins. By plotting missense mutations described so far on a 3D model of PHEX we observed that these mutations focus on two regions located in the inner part of the PHEX protein. Family members of 13 sporadic cases were analyzed and a PHEX mutation was detected in one of the apparently healthy mother. These results highlight the major role of PHEX in X-linked dominant hypophosphatemic rickets, and give new clues regarding the genetic analysis of the disease. A screening of the different family members should be mandatory when a PHEX mutation is assessed in a sporadic case and the search for another PHEX mutation should be systematically proceed when facing a missense mutation.
authors.affiliation: Inserm U561, Hôpital Saint-Vincent-de-Paul, 82 avenue Denfert-Rochereau, 75014, Paris, France. celine.gaucher@parisdescartes.fr
authors.forename: Céline
authors.initials: C
authors.lastname: Gaucher
authors.forename: Odile
authors.initials: O
authors.lastname: Walrant-Debray
authors.forename: Thy-Minh
authors.initials: TM
authors.lastname: Nguyen
authors.forename: Laure
authors.initials: L
authors.lastname: Esterle
authors.forename: Michèle
authors.initials: M
authors.lastname: Garabédian
authors.forename: Frédéric
authors.initials: F
authors.lastname: Jehan
mesh_terms: D020121:5' Untranslated Regions; D001483:Base Sequence; D018389:Codon, Nonsense; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D053098:Familial Hypophosphatemic Rickets / Q000201:enzymology* / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D040181:Genetic Diseases, X-Linked; D006801:Humans; D007438:Introns; D008297:Male; D008958:Models, Molecular; D016254:Mutagenesis, Insertional; D009154:Mutation; D020125:Mutation, Missense; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D011487:Protein Conformation; D022821:RNA Splice Sites; D017384:Sequence Deletion
chemical_list: D020121:5' Untranslated Regions; D018389:Codon, Nonsense; D017931:DNA Primers; D022821:RNA Splice Sites; D004247:DNA; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506231:PHEX protein, human