Genotype–phenotype analysis, and assessment of the importance of the zinc-binding site in PHEX in Japanese patients with X-linked hypophosphatemic rickets using 3D structure modeling

Ishihara, Yasuki; Ohata, Yasuhisa; Takeyari, Shinji; Kitaoka, Taichi; Fujiwara, M.; Nakano, Yoshifumi; Yamada, Chieko; Yamamoto, Katsusuke; Michigami, Toshimi; Mabe, Hiroyo; Yamaguchi, Takeshi; Matsui, Katsuyuki; Tamada, Izumi; Namba, Noriyuki; Yamamoto, Akiko; Etoh, Junya; Kawaguchi, Azusa; Kosugi, Rieko; Ozono, Keiichi; Kubota, Takuo

doi:10.1016/j.bone.2021.116135

Cited by 11 publications

(7 citation statements)

References 55 publications

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“…( 38 , 41 ) Notably, in Asian cohorts, because of the overall high prevalence of nutritional rickets due to vitamin D deficiency, XLH patients may also have concurrent vitamin D deficiency (43.6%–59.8%), which may in turn mask the diagnosis of XLH. ( 33 , 75 ) With regard to PTH levels, XLH patients have higher levels versus healthy controls, although when compared with calcium‐deficient rickets, these levels are still within the upper bounds of normal or only slightly elevated. ( 12 , 44 )…”

Section: Discussionmentioning

confidence: 99%

Asia‐Pacific Consensus Recommendations on X‐Linked Hypophosphatemia: Diagnosis, Multidisciplinary Management, and Transition From Pediatric to Adult Care

Munns

Yoo

et al. 2023

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X-linked hypophosphatemia (XLH) is a rare, inherited, multisystem disorder characterized by hypophosphatemia that occurs secondary to renal phosphate wasting. Mutations in PHEX gene (located at Xp22.1) in XLH alter bone mineral metabolism, resulting in diverse skeletal, dental, and other extraskeletal abnormalities that become evident in early childhood and persist into adolescence and adult life. XLH impacts physical function, mobility, and quality of life, and is associated with substantial socioeconomic burden and health care resource utilization. As the burden of illness varies with age, an appropriate transition of care from childhood and adolescence to adulthood is necessary to meet growth-related changes and minimize long-term sequelae of the condition. Previous XLH guidelines that encompassed transition of care have focused on Western experience. Regional differences in resource availability warrant tailoring of recommendations to the Asia-Pacific (APAC) context. Hence, a core expert panel of 15 pediatric and adult endocrinologists from nine countries/regions across APAC convened to formulate evidence-based recommendations for optimizing XLH care. A comprehensive literature search on PubMed using MeSH and free-text terms relevant to predetermined clinical questions on diagnosis, multidisciplinary management, and transition of care of XLH revealed 2171 abstracts. The abstracts were reviewed independently by two authors to shortlist a final of 164 articles. A total of 92 full-text articles were finally selected for data extraction and drafting the consensus statements. Sixteen guiding statements were developed based on review of evidence and real-world clinical experience. The GRADE criteria were used to appraise the quality of evidence supporting the statements. Subsequently, a DelphiThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Section: Discussionmentioning

confidence: 99%

Asia‐Pacific Consensus Recommendations on X‐Linked Hypophosphatemia: Diagnosis, Multidisciplinary Management, and Transition From Pediatric to Adult Care

Munns

Yoo

et al. 2023

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“…We recently examined the genotype-phenotype relationship in 39 Japanese patients with XLH using 3-dimensional structure modeling. Serum levels of intact FGF23 were significantly higher in patients with PHEX variants causing defects in zincbinding sites or cavities in the putative products, which suggested that these regions are crucial for the functions of PHEX proteins [76].…”

Section: Fgf23-related Hyperphosphatemic and Hypophosphatemic Disordersmentioning

confidence: 99%

Advances in understanding of phosphate homeostasis and related disorders

Michigami

2022

Endocr J

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Inorganic phosphate (Pi) in the mammalian body is balanced by its influx and efflux through the intestines, kidneys, bones, and soft tissues, at which several sodium/Pi co-transporters mediate its active transport. Pi homeostasis is achieved through the complex counter-regulatory feedback balance between fibroblast growth factor 23 (FGF23), 1,25-dihydroxyvitamin D (1,25(OH) 2 D), and parathyroid hormone. FGF23, which is mainly produced by osteocytes in bone, plays a central role in Pi homeostasis and exerts its effects by binding to the FGF receptor (FGFR) and αKlotho in distant target organs. In the kidneys, the main target, FGF23 promotes the excretion of Pi and suppresses the production of 1,25(OH) 2 D. Deficient and excess FGF23 result in hyperphosphatemia and hypophosphatemia, respectively. FGF23-related hypophosphatemic rickets/osteomalacia include tumor-induced osteomalacia and various genetic diseases, such as X-linked hypophosphatemic rickets. Coverage by the national health insurance system in Japan for the measurement of FGF23 and the approval of burosumab, an FGF23-neutralizing antibody, have had a significant impact on the diagnosis and treatment of FGF23-related hypophosphatemic rickets/osteomalacia. Some of the molecules responsible for genetic hypophosphatemic rickets/osteomalacia are highly expressed in osteocytes and function as local regulators of FGF23 production. A number of systemic factors also regulate FGF23 levels. Although the mechanisms responsible for Pi sensing in mammals have not yet been elucidated in detail, recent studies have suggested the involvement of FGFR1. The further clarification of the mechanisms by which osteocytes detect Pi levels and regulate FGF23 production will lead to the development of better strategies to treat hyperphosphatemic and hypophosphatemic conditions.

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“…The PHEX protein is suggested to function as a cell surface-bound, zinc-dependent protease based on its structure ( 40 ): however, its precise physiological roles and the mechanisms by which its deficiency increases FGF23 levels remain elusive. Although there is no clear relationship between the PHEX genotype and clinical phenotype ( 41 ), a recent study using 3-dimensional modeling has suggested that serum FGF23 levels are higher in patients whose PHEX mutations affect the zinc-binding site or the cavity of the protein ( 42 ). Thus, these regions may be important for PHEX function to regulate FGF23.…”

Section: Osteocytes and The Pathogenesis Of Fgf23-related Hypophospha...mentioning

confidence: 99%

Osteocytes and the pathogenesis of hypophosphatemic rickets

Yamazaki

Michigami

2022

Front. Endocrinol.

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Since phosphorus is a component of hydroxyapatite, its prolonged deprivation affects bone mineralization. Fibroblast growth factor 23 (FGF23) is essential for maintaining phosphate homeostasis and is mainly produced by osteocytes. FGF23 increases the excretion of inorganic phosphate (Pi) and decreases the production of 1,25-dihydroxyvitamin D in the kidneys. Osteocytes are cells of osteoblastic lineage that have undergone terminal differentiation and become embedded in mineralized bone matrix. Osteocytes express FGF23 and other multiple genes responsible for hereditary hypophosphatemic rickets, which include phosphate-regulating gene homologous to endopeptidase on X chromosome (PHEX), dentin matrix protein 1 (DMP1), and family with sequence similarity 20, member C (FAM20C). Since inactivating mutations in PHEX, DMP1, and FAM20C boost the production of FGF23, these molecules might be considered as local negative regulators of FGF23. Mouse studies have suggested that enhanced FGF receptor (FGFR) signaling is involved in the overproduction of FGF23 in PHEX-deficient X-linked hypophosphatemic rickets (XLH) and DMP1-deficient autosomal recessive hypophosphatemic rickets type 1. Since FGFR is involved in the transduction of signals evoked by extracellular Pi, Pi sensing in osteocytes may be abnormal in these diseases. Serum levels of sclerostin, an inhibitor Wnt/β-catenin signaling secreted by osteocytes, are increased in XLH patients, and mouse studies have suggested the potential of inhibiting sclerostin as a new therapeutic option for the disease. The elucidation of complex abnormalities in the osteocytes of FGF23-related hypophosphatemic diseases will provide a more detailed understanding of their pathogenesis and more effective treatments.

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Genotype–phenotype analysis, and assessment of the importance of the zinc-binding site in PHEX in Japanese patients with X-linked hypophosphatemic rickets using 3D structure modeling

Cited by 11 publications

References 55 publications

Asia‐Pacific Consensus Recommendations on X‐Linked Hypophosphatemia: Diagnosis, Multidisciplinary Management, and Transition From Pediatric to Adult Care

Asia‐Pacific Consensus Recommendations on X‐Linked Hypophosphatemia: Diagnosis, Multidisciplinary Management, and Transition From Pediatric to Adult Care

Advances in understanding of phosphate homeostasis and related disorders

Osteocytes and the pathogenesis of hypophosphatemic rickets

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