Genetic diagnosis of X-linked dominant hypophosphatemic rickets in a cohort study: Tubular reabsorption of phosphate and 1,25(OH)2D serum levels are associated with PHEX mutation type

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Abstract

Background

Genetic Hypophosphatemic Rickets (HR) is a group of diseases characterized by renal phosphate wasting with inappropriately low or normal 1,25-dihydroxyvitamin D ₃(1,25(OH) ₂D) serum levels. The most common form of HR is X-linked dominant HR (XLHR) which is caused by inactivating mutations in the PHEX gene. The purpose of this study was to perform genetic diagnosis in a cohort of patients with clinical diagnosis of HR, to perform genotype-phenotype correlations of those patients and to compare our data with other HR cohort studies.

Methods

Forty three affected individuals from 36 non related families were analyzed. For the genetic analysis, the PHEX gene was sequenced in all of the patients and in 13 cases the study was complemented by mRNA sequencing and Multiple Ligation Probe Assay. For the genotype-phenotype correlation study, the clinical and biochemical phenotype of the patients was compared with the type of mutation, which was grouped into clearly deleterious or likely causative, using the Mann-Whitney and Fisher's exact test.

Results

Mutations in the PHEX gene were identified in all the patients thus confirming an XLHR. Thirty four different mutations were found distributed throughout the gene with higher density at the 3' end. The majority of the mutations were novel (69.4%), most of them resulted in a truncated PHEX protein (83.3%) and were family specific (88.9%). Tubular reabsorption of phosphate (TRP) and 1,25(OH) ₂D serum levels were significantly lower in patients carrying clearly deleterious mutations than in patients carrying likely causative ones (61.39 ± 19.76 vs. 80.14 ± 8.80%, p = 0.028 and 40.93 ± 30.73 vs. 78.46 ± 36.27 pg/ml, p = 0.013).

Conclusions

PHEX gene mutations were found in all the HR cases analyzed, which was in contrast with other cohort studies. Patients with clearly deleterious PHEX mutations had lower TRP and 1,25(OH) ₂D levels suggesting that the PHEX type of mutation might predict the XLHR phenotype severity.

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Most cited references 34

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Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23.

(2000)

Proper serum phosphate concentrations are maintained by a complex and poorly understood process. Identification of genes responsible for inherited disorders involving disturbances in phosphate homeostasis may provide insight into the pathways that regulate phosphate balance. Several hereditary disorders of isolated phosphate wasting have been described, including X-linked hypophosphataemic rickets (XLH), hypophosphataemic bone disease (HBD), hereditary hypophosphataemic rickets with hypercalciuria (HHRH) and autosomal dominant hypophosphataemic rickets (ADHR). Inactivating mutations of the gene PHEX, encoding a member of the neutral endopeptidase family of proteins, are responsible for XLH (refs 6,7). ADHR (MIM 193100) is characterized by low serum phosphorus concentrations, rickets, osteomalacia, lower extremity deformities, short stature, bone pain and dental abscesses. Here we describe a positional cloning approach used to identify the ADHR gene which included the annotation of 37 genes within 4 Mb of genomic sequence. We identified missense mutations in a gene encoding a new member of the fibroblast growth factor (FGF) family, FGF23. These mutations in patients with ADHR represent the first mutations found in a human FGF gene.

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Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia.

T Shimada, S Mizutani, T Muto … (2001)

Tumor-induced osteomalacia (TIO) is one of the paraneoplastic diseases characterized by hypophosphatemia caused by renal phosphate wasting. Because removal of responsible tumors normalizes phosphate metabolism, an unidentified humoral phosphaturic factor is believed to be responsible for this syndrome. To identify the causative factor of TIO, we obtained cDNA clones that were abundantly expressed only in a tumor causing TIO and constructed tumor-specific cDNA contigs. Based on the sequence of one major contig, we cloned 2,270-bp cDNA, which turned out to encode fibroblast growth factor 23 (FGF23). Administration of recombinant FGF23 decreased serum phosphate in mice within 12 h. When Chinese hamster ovary cells stably expressing FGF23 were s.c. implanted into nude mice, hypophosphatemia with increased renal phosphate clearance was observed. In addition, a high level of serum alkaline phosphatase, low 1,25-dihydroxyvitamin D, deformity of bone, and impairment of body weight gain became evident. Histological examination showed marked increase of osteoid and widening of growth plate. Thus, continuous production of FGF23 reproduced clinical, biochemical, and histological features of TIO in vivo. Analyses for recombinant FGF23 products produced by Chinese hamster ovary cells indicated proteolytic cleavage of FGF23 at the RXXR motif. Recent genetic study indicates that missense mutations in this RXXR motif of FGF23 are responsible for autosomal dominant hypophosphatemic rickets, another hypophosphatemic disease with similar features to TIO. We conclude that overproduction of FGF23 causes TIO, whereas mutations in the FGF23 gene result in autosomal dominant hypophosphatemic rickets possibly by preventing proteolytic cleavage and enhancing biological activity of FGF23.

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A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. The HYP Consortium.

J Murken, H Lehrach, S. Pannetier … (1995)

X-linked hypophosphatemic rickets (HYP) is a dominant disorder characterised by impaired phosphate uptake in the kidney, which is likely to be caused by abnormal regulation of sodium phosphate cotransport in the proximal tubules. By positional cloning, we have isolated a candidate gene from the HYP region in Xp22.1. This gene exhibits homology to a family of endopeptidase genes, members of which are involved in the degradation or activation of a variety of peptide hormones. This gene (which we have called PEX) is composed of multiple exons which span at least five cosmids. Intragenic non-overlapping deletions from four different families and three mutations (two splice sites and one frameshift) have been detected in HYP patients, which suggest that the PEX gene is involved in the HYP disorder.

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Author and article information

Journal

Journal ID (nlm-ta): BMC Med Genet

Title: BMC Medical Genetics

Publisher: BioMed Central

ISSN (Electronic): 1471-2350

Publication date Collection: 2011

Publication date (Electronic): 8 September 2011

Volume: 12

Page: 116

Affiliations

[1 ]Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain

[2 ]Unidad de Endocrinología Pediátrica, Crecimiento y Adolescencia. Pediatría, Hospital Clínico Universitario y Universidad de Santiago de Compostela, Spain

[3 ]Pediatría. Hospital Clínico Universitario, Santiago de Compostela, Spain

[4 ]Endocrinología, Hospital Clínico Universitario, Santiago de Compostela, Spain

[5 ]Pediatría, Complejo Hospitalario de Pontevedra, Spain

[6 ]Pediatría, Complejo Hospitalario de Vigo, Spain

[7 ]Pediatría, Hospital de Cruces, Barakaldo, Spain

[8 ]Nefrología Pediátrica, Hospital Vall d'Hebrón, Barcelona, Spain

[9 ]Genética, Hospital San Joan de Deu, Espluges-Barcelona, Spain

[10 ]Nefrología, Hospital San Joan de Deu, Espluges-Barcelona, Spain

[11 ]Pediatría, Hospital Virgen de la Salud, Elda, Spain

[12 ]Genética, Hospital Universitario Marqués de Valdecilla, Santander, Spain

[13 ]Pediatría, Fundación Jiménez Díaz, Madrid, Spain

[14 ]Genética, Hospital Ramón y Cajal, Madrid, Spain

[15 ]Genética, Hospital Universitario La Paz, Madrid, Spain

[16 ]Genética, Complejo Hospitalario A Coruña, Spain

[17 ]Genética, Hospital Donostia, San Sebastián, Spain

[18 ]Pediatría, Hospital Donostia, San Sebastián, Spain

[19 ]Genética, Hospital Reina Sofía, Córdoba, Spain

[20 ]Genética, Hospital La Fé and CIBERER, Valencia, Spain

[21 ]Genética, Hospital Santa María, Lisboa, Portugal

[22 ]Pediatría, Complejo Hospitalario de Toledo. Spain

Article

Publisher ID: 1471-2350-12-116

DOI: 10.1186/1471-2350-12-116

PMC ID: 3189111

PubMed ID: 21902834

SO-VID: ccf65ced-03ea-4154-9d9a-0c7d07f7149e

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.