Function of PHEX mutations p.Glu145* and p.Trp749Arg in families with X-linked hypophosphatemic rickets by the negative regulation mechanism on FGF23 promoter transcription

Gan, Yu-Mian; Zhang, Yanping; Ruan, Dan-Dan; Huang, Jianbin; Zhu, Yao‐Bin; Lin, Xin-Fu; Xiao, Xiaoping; Cheng, Qian; Geng, Zhen-bo; Liao, Lisheng; Tang, Fa-Qiang; Luo, Jie‐Wei

doi:10.1038/s41419-022-04969-5

Cited by 6 publications

(5 citation statements)

References 41 publications

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“…It is predominantly expressed in osteoblasts, osteocytes, cartilage, and odontoblasts, and in these cells, PHEX deficiencies impair the cellular trafficking, endopeptidase activity, and FGF23 signaling that, in turn, reduce renal phosphate reabsorption, resulting in abnormal bone mineralization and hypophosphatemia [7]. The regulatory mechanism between PHEX and FGF23 remains unclear, but a recent study demonstrated that PHEX is a direct transcriptional inhibitor of the FGF23 gene [28].…”

Section: Discussionmentioning

confidence: 99%

De Novo Large Deletions in the PHEX Gene Caused X-Linked Hypophosphataemic Rickets in Two Italian Female Infants Successfully Treated with Burosumab

Pecoraro,

Fioretti,

Perruno

et al. 2023

Diagnostics

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Pathogenic variants in the PHEX gene cause rare and severe X-linked dominant hypophosphataemia (XLH), a form of heritable hypophosphatemic rickets (HR) characterized by renal phosphate wasting and elevated fibroblast growth factor 23 (FGF23) levels. Burosumab, the approved human monoclonal anti-FGF23 antibody, is the treatment of choice for XLH. The genetic and phenotypic heterogeneity of HR often delays XLH diagnoses, with critical effects on disease course and therapy. We herein report the clinical and genetic features of two Italian female infants with sporadic HR who successfully responded to burosumab. Their diagnoses were based on clinical and laboratory findings and physical examinations. Next-generation sequencing (NGS) of the genes associated with inherited HR and multiple ligation probe amplification (MLPA) analysis of the PHEX and FGF23 genes were performed. While a conventional analysis of the NGS data did not reveal pathogenic or likely pathogenic small nucleotide variants (SNVs) in the known HR-related genes, a quantitative analysis identified two different heterozygous de novo large intragenic deletions in PHEX, and this was confirmed by MLPA. Our molecular data indicated that deletions in the PHEX gene can be the cause of a significant fraction of XLH; hence, their presence should be evaluated in SNV-negative female patients. Our patients successfully responded to burosumab, demonstrating the efficacy of this drug in the treatment of XLH. In conclusion, the execution of a phenotype-oriented genetic test, guided by known types of variants, including the rarest ones, was crucial to reach the definitive diagnoses and ensure our patients of long-term therapy administration.

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Section: Discussionmentioning

confidence: 99%

De Novo Large Deletions in the PHEX Gene Caused X-Linked Hypophosphataemic Rickets in Two Italian Female Infants Successfully Treated with Burosumab

Pecoraro,

Fioretti,

Perruno

et al. 2023

Diagnostics

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“…In addition, PHEX may mediate hypophosphatemia by regulating the FGF23 promoter to regulate FGF23 concentration. Therefore, PHEX is a direct transcriptional inhibitor of FGF23 and affects the expression of FGF23 (Gan et al, 2022). Excess and deficiency of FGF23 lead to hypophosphatemia and hyperphosphatemia (see part 4.5), respectively (Fukumoto, 2016).…”

Section: Fgf23 and Related Adhrmentioning

confidence: 99%

Hereditary dentin defects with systemic diseases

Zhu

Wang

et al. 2023

Oral Diseases

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ObjectiveThis review aimed to summarize recent progress on syndromic dentin defects, promoting a better understanding of systemic diseases with dentin malformations, the molecules involved, and related mechanisms.Subjects and MethodsReferences on genetic diseases with dentin malformations were obtained from various sources, including PubMed, OMIM, NCBI, and other websites. The clinical phenotypes and genetic backgrounds of these diseases were then summarized, analyzed, and compared.ResultsOver 10 systemic diseases, including osteogenesis imperfecta, hypophosphatemic rickets, vitamin D‐dependent rickets, familial tumoral calcinosis, Ehlers‐Danlos syndrome, Schimke immuno‐osseous dysplasia, hypophosphatasia, Elsahy‐Waters syndrome, Singleton‐Merten syndrome, odontochondrodysplasia, and microcephalic osteodysplastic primordial dwarfism type II were examined. Most of these are bone disorders, and their pathogenic genes may regulate both dentin and bone development, involving extracellular matrix, cell differentiation, and metabolism of calcium, phosphorus, and vitamin D. The phenotypes of these syndromic dentin defects various with the involved genes, part of them are similar to dentinogenesis imperfecta or dentin dysplasia, while others only present one or two types of dentin abnormalities such as discoloration, irregular enlarged or obliterated pulp and canal, or root malformation.ConclusionSome specific dentin defects associated with systemic diseases may serve as important phenotypes for dentists to diagnose. Furthermore, mechanistic studies on syndromic dentin defects may provide valuable insights into isolated dentin defects and general dentin development or mineralization.

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“…The PHEX gene contains 22 exons that code for a protein of 749 amino acids, with more than 400 mutations having been recorded so far ( 2 January 2023). However, the mechanism by which these mutations increase FGF23 levels has not been fully elucidated, with preliminary evidence that PHEX is a direct transcriptional inhibitor of FGF23 and is involved in its expression [ 39 ]. There are sporadic cases (between 30 and 54%, depending on the series), in which the PHEX gene mutation frequency is lower than in familial cases.…”

Section: Etiology Of Osteomalaciamentioning

confidence: 99%

Osteomalacia in Adults: A Practical Insight for Clinicians

Arboleya

Braña

Pardo

et al. 2023

JCM

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The term osteomalacia (OM) refers to a series of processes characterized by altered mineralization of the skeleton, which can be caused by various disorders of mineral metabolism. OM can be genetically determined or occur due to acquired disorders, among which the nutritional origin is particularly relevant, due to its wide epidemiological extension and its nature as a preventable disease. Among the hereditary diseases associated with OM, the most relevant is X-linked hypophosphatemia (XLH), which manifests in childhood, although its consequences persist into adulthood where it can acquire specific clinical characteristics, and, although rare, there are XLH cases that reach the third or fourth decade of life without a diagnosis. Some forms of OM present very subtle initial manifestations which cause both considerable diagnosis and treatment delay. On occasions, the presence of osteopenia and fragility fractures leads to an erroneous diagnosis of osteoporosis, which may imply the prescription of antiresorptive drugs (i.e., bisphosphonates or denosumab) with catastrophic consequences for OM bone. On the other hand, some radiological features of OM can be confused with those of axial spondyloarthritis and lead to erroneous diagnoses. The current prevalence of OM is not known and is very likely that its incidence is much higher than previously thought. Moreover, OM explains part of the therapeutic failures that occur in patients diagnosed with other bone diseases. Therefore, it is essential that clinicians who treat adult skeletal diseases take into account the considerations provided in this practical review when focusing on the diagnosis and treatment of their patients with bone diseases.

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Function of PHEX mutations p.Glu145* and p.Trp749Arg in families with X-linked hypophosphatemic rickets by the negative regulation mechanism on FGF23 promoter transcription

Cited by 6 publications

References 41 publications

De Novo Large Deletions in the PHEX Gene Caused X-Linked Hypophosphataemic Rickets in Two Italian Female Infants Successfully Treated with Burosumab

De Novo Large Deletions in the PHEX Gene Caused X-Linked Hypophosphataemic Rickets in Two Italian Female Infants Successfully Treated with Burosumab

Hereditary dentin defects with systemic diseases

Osteomalacia in Adults: A Practical Insight for Clinicians

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