Identification of a novel loss-of-function PHEX mutation, Ala720Ser, in a sporadic case of adult-onset hypophosphatemic osteomalacia.

2.50
Hdl Handle:
http://hdl.handle.net/11287/620762
Title:
Identification of a novel loss-of-function PHEX mutation, Ala720Ser, in a sporadic case of adult-onset hypophosphatemic osteomalacia.
Authors:
Goljanek-Whysall, K.; Tridimas, A.; McCormick, R.; Russell, N-J; Sloman, Melissa; Sorani, A.; Fraser, W. D.; Hannan, F. M.
Abstract:
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.
Citation:
Identification of a novel loss-of-function PHEX mutation, Ala720Ser, in a sporadic case of adult-onset hypophosphatemic osteomalacia. 2018, 106:30-34 Bone
Publisher:
Elsevier
Journal:
Bone
Issue Date:
Jan-2018
URI:
http://hdl.handle.net/11287/620762
DOI:
10.1016/j.bone.2017.10.002
PubMed ID:
28982589
Additional Links:
https://linkinghub.elsevier.com/retrieve/pii/S8756-3282(17)30360-5
Type:
Case Report
Language:
en
ISSN:
1873-2763
Appears in Collections:
Molecular Genetics; 2018 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorGoljanek-Whysall, K.en
dc.contributor.authorTridimas, A.en
dc.contributor.authorMcCormick, R.en
dc.contributor.authorRussell, N-Jen
dc.contributor.authorSloman, Melissaen
dc.contributor.authorSorani, A.en
dc.contributor.authorFraser, W. D.en
dc.contributor.authorHannan, F. M.en
dc.date.accessioned2018-07-11T13:45:39Z-
dc.date.available2018-07-11T13:45:39Z-
dc.date.issued2018-01-
dc.identifier.citationIdentification of a novel loss-of-function PHEX mutation, Ala720Ser, in a sporadic case of adult-onset hypophosphatemic osteomalacia. 2018, 106:30-34 Boneen
dc.identifier.issn1873-2763-
dc.identifier.pmid28982589-
dc.identifier.doi10.1016/j.bone.2017.10.002-
dc.identifier.urihttp://hdl.handle.net/11287/620762-
dc.description.abstractAdults 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.en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.urlhttps://linkinghub.elsevier.com/retrieve/pii/S8756-3282(17)30360-5en
dc.rightsArchived with thanks to Boneen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.subject.meshAdult-
dc.subject.meshDNA Mutational Analysis-
dc.subject.meshFemale-
dc.subject.meshFibroblast Growth Factors-
dc.subject.meshGenetic Diseases, X-Linked-
dc.subject.meshHEK293 Cells-
dc.subject.meshHumans-
dc.subject.meshHypophosphatemia-
dc.subject.meshMutation-
dc.subject.meshOsteomalacia-
dc.subject.meshPHEX Phosphate Regulating Neutral Endopeptidase-
dc.titleIdentification of a novel loss-of-function PHEX mutation, Ala720Ser, in a sporadic case of adult-onset hypophosphatemic osteomalacia.en
dc.typeCase Reporten
dc.identifier.journalBoneen
dc.type.versionPublisheden

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