Hypophosphatemic Rickets (HR) is a relatively rare disease with an incidence of approximately 1 in 25,000. It is primarily caused by genetic or acquired factors leading to excessive renal phosphate excretion, resulting in severely low blood phosphate levels and impaired bone mineralization. In childhood, it manifests as frontal bossing, pigeon chest, rachitic rosary, limb deformities (bowlegs or knock-knees), growth retardation, short stature, waddling gait, and dental abnormalities (enamel defects, recurrent dental abscesses). In adulthood, symptoms include bone pain, muscle weakness, multiple fractures, height loss, and restricted mobility.
 

Pathogenesis
 

Hypophosphatemic rickets is mainly classified into hereditary and acquired types:

I) Hereditary TypesX-linked Dominant Hypophosphatemic Rickets (XLH): Caused by mutations in the PHEXgene, this is the most common hereditary type, accounting for about 80% of hereditary hypophosphatemic rickets cases.

● Autosomal Dominant Hypophosphatemic Rickets (ADHR): Caused by mutations in the FGF23gene, with the most common mutation site being c.527G>A (p.Arg176Gln).

● Autosomal Recessive Hypophosphatemic Rickets (ARHR): Includes subtypes caused by mutations in genes such as DMP1, ENPP1, and FAM20C.

● Hereditary Hypophosphatemia with Hypercalciuria (HHRH): Caused by mutations in the SLC34A3gene.
 

II) Acquired TypeTumor-Induced Osteomalacia (TIO): Caused by excessive secretion of FGF23 by certain benign tumors.

 

(Image placeholder: Hypophosphatemic rickets)

 

In most types, the core pathogenesis of hypophosphatemic rickets involves abnormal regulation of the FGF23-PHEX axis. Fibroblast Growth Factor 23 (FGF23) is a key regulator of phosphate metabolism, secreted by osteocytes and osteoblasts. The PHEXgene is located on chromosome Xp22.1, and its encoded PHEX protein is primarily expressed in osteocytes and osteoblasts.
 

Under normal physiological conditions, the PHEX protein interacts with N-linked glycoproteins (SIBLING proteins) such as DMP1, stabilizing a complex that inhibits FGF23 transcription and prevents the release of ASARM peptides that inhibit mineralization, thereby suppressing FGF23 expression. However, when the PHEXgene is mutated and inactivated, it leads to ASARM peptide accumulation, which directly inhibits bone mineralization and upregulates FGF23 expression. Additionally, it causes a significant increase in FGF23 transcription and synthesis in osteocytes. Elevated FGF23 negatively regulates serum 1,25-dihydroxyvitamin D [1,25-(OH)₂D] levels, thereby inhibiting phosphate reabsorption in the renal proximal tubules and intestines, while also reducing intestinal phosphate absorption. This ultimately results in persistent hypophosphatemia, leading to the skeletal clinical manifestations of rickets or osteomalacia.

 

Gene Therapy
 

Minicircle DNA (MC-DNA) Therapy: In October 2025, a study by the team of Xu Chao and Zhao Jiajun from Shandong Provincial Hospital published in Advanced Scienceshowed that using a minicircle DNA vector expressing the FGF23 fragment (amino acids 180-251) to treat XLH mouse models significantly improved blood phosphate levels, reduced serum alkaline phosphatase, and improved bone mineralization, with no significant adverse effects observed for at least 6 weeks.

Adeno-Associated Virus (AAV) Vector Therapy: Liver-targeted AAV vectors expressing the C-terminal tail of FGF23 can improve skeletal manifestations and osteomalacia in XLH mouse models.

 

Mouse Models
 

DMP1-KO Mice: Knockout of the DMP1gene, modeling Autosomal Recessive Hypophosphatemic Rickets (ARHR1). This model exhibits significantly elevated FGF23 levels, severe hypophosphatemia, and bone mineralization defects.

SLC34A3-KO Mice: Knockout of the Slc34a1gene, modeling Hereditary Hypophosphatemia with Hypercalciuria (HHRH), showing abnormal blood phosphate levels and skeletal lesions.

Hyp Mice: A classic hypophosphatemic rickets model with a mutation in the PHEXgene, leading to abnormal FGF23 expression and a series of symptoms similar to human hypophosphatemic rickets.

PHEX-T1349C Knock-in Mice: By introducing the T1349C mutation into the PHEXgene, this model can simulate hypophosphatemic rickets caused by specific PHEXgene mutations.

FGF23-R176Q Mice: With the R176Q mutation in the FGF23gene, leading to abnormal FGF23 function and subsequent phosphate metabolism disorders and skeletal lesions.

 

MingCeler Biotech Facilitates Gene Therapy Research
 

Gene therapy offers hope for rare diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has established multiple rare disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models. It enables editing at virtually any target genomic locus and can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as two months.

MingCeler Biotech can customize various HR mouse models according to client needs, such as DMP1-KO, SLC34A3-KO, Hyp, PHEX-T1349C knock-in, and FGF23-R176Q mice. We welcome inquiries.

 

References:

[1] Ding Guixia. New advances in hypophosphatemic rickets research. Chinese Journal of Applied Clinical Pediatrics, 2019, 34(17): 1304-1308. DOI: 10.3760/cma.j.issn.2095-428X.2019.17.006

[2] Jagtap VS, Sarathi V, Lila AR, Bandgar T, Menon P, Shah NS. Hypophosphatemic rickets. Indian J Endocrinol Metab. 2012 Mar;16(2):177-82. doi: 10.4103/2230-8210.93733. PMID: 22470852; PMCID: PMC3313733.

[3] Lorenz-Depiereux B, Benet-Pages A, Eckstein G, Tenenbaum-Rakover Y, Wagenstaller J, Tiosano D, Gershoni-Baruch R, Albers N, Lichtner P, Schnabel D, Hochberg Z, Strom TM. Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. Am J Hum Genet. 2006 Feb;78(2):193-201. doi: 10.1086/499410. Epub 2005 Dec 9. PMID: 16358215; PMCID: PMC1380229.
 

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