title: Mutational analysis of patients with FGF23-related hypophosphatemic rickets.
abstract: OBJECTIVE
  X-linked hypophosphatemic rickets (XLHR) caused by mutations in the PHEX gene is considered to be the most frequent cause of fibroblast growth factor 23 (FGF23)-related congenital hypophosphatemic rickets. In previous studies, mutations in the PHEX gene were detected in 60-70% of patients with clinical diagnoses of XLHR. This leads to the question whether current screening methods for mutations in the PHEX gene are inadequate or whether there is a substantial number of patients with other genetic causes of hypophosphatemic rickets. We conducted a genetic analysis of patients with FGF23-related hypophosphatemic rickets to clarify their etiology and evaluate the prevalence of XLHR among this group.
  
  
  METHODS
  We studied 27 patients with familial and sporadic congenital hypophosphatemic rickets in whom serum FGF23 was above 30 pg/ml using an assay for the full-length protein. Exons and exon-intron junctions of genomic DNA of causative genes for FGF23-related hypophosphatemic rickets were sequenced. PHEX mRNA from peripheral blood was analyzed in some patients.
  
  
  RESULTS
  Direct sequencing of genomic DNA identified 11 novel and four known mutations in the PHEX gene. Additionally, there was a large PHEX gene deletion in one case and abnormal PHEX mRNA splicing in another. In summary, 26 patients (96%) had XLHR and one patient had autosomal recessive hypophosphatemic rickets 2.
  
  
  CONCLUSIONS
  XLHR is by far the most prevalent cause of FGF23-related hypophosphatemic rickets. We propose that analysis of PHEX mRNA from peripheral blood would be appropriate for the first screening step in determining the etiology of FGF23-related hypophosphatemic rickets.
authors.affiliation: Division of Nephrology and Endocrinology, Department of Medicine, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kinoshita
authors.forename: Tasuku
authors.initials: T
authors.lastname: Saito
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Michiko
authors.initials: M
authors.lastname: Hori
authors.forename: Manabu
authors.initials: M
authors.lastname: Taguchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Igarashi
authors.forename: Seiji
authors.initials: S
authors.lastname: Fukumoto
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D016326:Extracellular Matrix Proteins / Q000235:genetics; D053098:Familial Hypophosphatemic Rickets / Q000097:blood / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics*; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood / Q000235:genetics / Q000502:physiology*; D040181:Genetic Diseases, X-Linked; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008403:Mass Screening; D008875:Middle Aged; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000032:analysis / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics; D010727:Phosphoric Diester Hydrolases / Q000235:genetics; D011755:Pyrophosphatases / Q000235:genetics; D055815:Young Adult
chemical_list: C513309:DMP1 protein, human; D016326:Extracellular Matrix Proteins; C000717427:FGF23 protein, human; D010750:Phosphoproteins; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506231:PHEX protein, human; D011755:Pyrophosphatases