Identification of a novel loss-of-function PHEX mutation, Ala720Ser, in a sporadic case of adult-onset hypophosphatemic osteomalacia
| Autor: | Nicki-Jayne Russell, Andreas Tridimas, Katarzyna Goljanek-Whysall, Fadil M. Hannan, Rachel McCormick, Melissa Sloman, William D. Fraser, Alan Sorani |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Adult
0301 basic medicine medicine.medical_specialty Histology Hypophosphatemia Physiology Endocrinology Diabetes and Metabolism DNA Mutational Analysis Mutant Rickets medicine.disease_cause Germline 03 medical and health sciences Mutant protein Internal medicine Humans Medicine Mutation Osteomalacia business.industry PHEX Genetic Diseases X-Linked medicine.disease PHEX Phosphate Regulating Neutral Endopeptidase Fibroblast Growth Factors Fibroblast Growth Factor-23 HEK293 Cells 030104 developmental biology Endocrinology Female business |
| Zdroj: | Bone |
| Popis: | Adults presenting with sporadic hypophosphatemia and elevations in circulating fibroblast growth factor-23 (FGF23) concentrations are usually investigated for an acquired disorder of FGF23 excess such as tumor induced osteomalacia (TIO). However, in some cases the underlying tumor is not detected, and such patients may harbor other causes of FGF23 excess. Indeed, coding-region and 3’UTR mutations of phosphate-regulating neutral endopeptidase (PHEX), which encodes a cell-surface protein that regulates circulating FGF23 concentrations, can lead to alterations in phosphate homeostasis, which are not detected until adulthood. Here, we report an adult female who presented with hypophosphatemic osteomalacia and raised serum FGF23 concentrations. The patient and her parents, who were her only first-degree relatives, had no history of rickets. The patient was thus suspected of having TIO. However, no tumor had been identified following extensive localization studies. Mutational analysis of the PHEX coding-region and 3’UTR was undertaken, and this revealed the patient to be heterozygous for a novel germline PHEX mutation (c.2158G > T; p.Ala720Ser). In vitro studies involving the expression of WT and mutant PHEX proteins in HEK293 cells demonstrated the Ala720Ser mutation to impair trafficking of PHEX, with ~ 20% of the mutant protein being expressed at the cell surface, compared to ~ 80% cell surface expression for WT PHEX (p < 0.05). Thus, our studies have identified a pathogenic PHEX mutation in a sporadic case of adult-onset hypophosphatemic osteomalacia, and these findings highlight a role for PHEX gene analysis in some cases of suspected TIO, particularly when no tumor has been identified. |
| Databáze: | OpenAIRE |
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