{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T23:43:35Z","timestamp":1772754215074,"version":"3.50.1"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,12,5]],"date-time":"2023-12-05T00:00:00Z","timestamp":1701734400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>A Chinese family was identified to have two patients with rickets, an adult female and a male child (proband), both exhibiting signs related to X-linked hypophosphatemic rickets (XLH). Gene sequencing analysis revealed a deletion of adenine at position 1985 (c.1985delA) in the <jats:italic>PHEX<\/jats:italic>-encoding gene. To investigate the relationship between this mutation and the pathogenicity of XLH, as well as analyze the effects of different dosages of <jats:italic>PHEX<\/jats:italic> gene mutations on clinical phenotypes, we developed a rat model carrying the <jats:italic>PHEX<\/jats:italic> deletion mutation. The CRISPR\/Cas9 gene editing technology was employed to construct the rat model with the <jats:italic>PHEX<\/jats:italic> gene mutation (c.1985delA). Through reproductive procedures, five genotypes of rats were obtained: female wild type (X\/X), female heterozygous (-\/X), female homozygous wild type (-\/-), male wild type (X\/Y), and male hemizygous (-\/Y). The rats with different genotypes underwent analysis of growth, serum biochemical parameters, and bone microstructure. The results demonstrated the successful generation of a stable rat model inheriting the <jats:italic>PHEX<\/jats:italic> gene mutation. Compared to the wild-type rats, the mutant rats displayed delayed growth, shorter femurs, and significantly reduced bone mass. Among the female rats, the homozygous individuals exhibited the smallest body size, decreased bone mass, shortest femur length, and severe deformities. Moreover, the mutant rats showed significantly lower blood phosphorus concentration, elevated levels of FGF23 and alkaline phosphatase, and increased expression of phosphorus regulators. In conclusion, the XLH rat model with the <jats:italic>PHEX<\/jats:italic> gene mutation dosage demonstrated its impact on growth and development, serum biochemical parameters, and femoral morphology.<\/jats:p>","DOI":"10.3389\/fendo.2023.1251718","type":"journal-article","created":{"date-parts":[[2023,12,5]],"date-time":"2023-12-05T05:13:40Z","timestamp":1701753220000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["The contribution of a novel PHEX gene mutation to X-linked hypophosphatemic rickets: a case report and an analysis of the gene mutation dosage effect in a rat model"],"prefix":"10.3389","volume":"14","author":[{"given":"Xiaoming","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cijing","family":"Cai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaocong","family":"Lun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiuli","family":"Ye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weiyuan","family":"Pan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yushi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuexuan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taoshan","family":"Feng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Faming","family":"Su","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Choudi","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaxin","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meilian","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guoda","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,12,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-08-0818","article-title":"Incidence and prevalence of nutritional and hereditary rickets in southern Denmark","volume":"160","author":"Beck-Nielsen","year":"2009","journal-title":"Eur J Endocrinol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s00198-022-06385-z","article-title":"Lower limb bone geometry in adult individuals with X-linked hypophosphatemia: an observational study","volume":"33","author":"Scorcelletti","year":"2022","journal-title":"Osteoporos Int"},{"key":"B3","doi-asserted-by":"publisher","first-page":"563","DOI":"10.3390\/life11060563","article-title":"The metabolic bone disease X-linked hypophosphatemia: case presentation, pathophysiology and pharmacology","volume":"11","author":"Vincze","year":"2021","journal-title":"Life (Basel)"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/ng1095-130","article-title":"A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. The HYP Consortium","volume":"11","author":"Francis","year":"1995","journal-title":"Nat Genet"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1210\/er.2017-00220","article-title":"X-linked hypophosphatemia and FGF23-related hypophosphatemic diseases: prospect for new treatment","volume":"39","author":"Kinoshita","year":"2018","journal-title":"Endocr Rev"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1148\/radiology.171.2.2539609","article-title":"X-linked hypophosphatemia in adults: prevalence of skeletal radiographic and scintigraphic features","volume":"171","author":"Hardy","year":"1989","journal-title":"Radiology"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1097\/00005792-198911000-00002","article-title":"X-linked hypophosphatemia: a clinical, biochemical, and histopathologic assessment of morbidity in adults","volume":"68","author":"Reid","year":"1989","journal-title":"Med (Baltimore)"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.86.8.7761","article-title":"Mutational analysis and genotype-phenotype correlation of the PHEX gene in X-linked hypophosphatemic rickets","volume":"86","author":"Holm","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-15-0515","article-title":"Hereditary hypophosphatemia in Norway: a retrospective population-based study of genotypes, phenotypes, and treatment complications","volume":"174","author":"Rafaelsen","year":"2016","journal-title":"Eur J Endocrinol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s00223-010-9373-0","article-title":"Phenotype presentation of hypophosphatemic rickets in adults","volume":"87","author":"Beck-Nielsen","year":"2010","journal-title":"Calcif Tissue Int"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1203\/01.PDR.0000169983.40758.7B","article-title":"A clinical and molecular genetic study of hypophosphatemic rickets in children","volume":"58","author":"Cho","year":"2005","journal-title":"Pediatr Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.81.11.8923863","article-title":"X-linked hypophosphatemia: a search for gender, race, anticipation, or parent of origin effects on disease expression in children","volume":"81","author":"Whyte","year":"1996","journal-title":"J Clin Endocrinol Metab"},{"key":"B13","article-title":"X-linked hypophosphatemia: the mutant gene is expressed in teeth as well as in kidney","volume":"46","author":"Shields","year":"1990","journal-title":"Am J Hum Genet"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.5650070602","article-title":"X-linked hypophosphatemic rickets: a study (with literature review) of linear growth response to calcitriol and phosphate therapy","volume":"7","author":"Petersen","year":"1992","journal-title":"J Bone Miner Res"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2019.01.021","article-title":"Clinical and genetic analysis in a large Chinese cohort of patients with X-linked hypophosphatemia","volume":"121","author":"Zhang","year":"2019","journal-title":"Bone"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s00223-013-9736-4","article-title":"Dosage effect of a Phex mutation in a murine model of X-linked hypophosphatemia","volume":"93","author":"Ichikawa","year":"2013","journal-title":"Calcif Tissue Int"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.544","article-title":"A Phex mutation in a murine model of X-linked hypophosphatemia alters phosphate responsiveness of bone cells","volume":"27","author":"Ichikawa","year":"2012","journal-title":"J Bone Miner Res"},{"key":"B18","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1002\/jbmr.3923","article-title":"Sclerostin antibody treatment increases bone mass and normalizes circulating phosphate levels in growing hyp mice","volume":"35","author":"Carpenter","year":"2020","journal-title":"J Bone Miner Res"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(99)80151-1","article-title":"X-chromosome inactivation","volume":"9","author":"Lyon","year":"1999","journal-title":"Curr Biol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2012.10.012","article-title":"Novel and de novo PHEX mutations in patients with hypophosphatemic rickets","volume":"52","author":"Durmaz","year":"2013","journal-title":"Bone"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1356","DOI":"10.3390\/genes13081356","article-title":"PHEXL222P mutation increases phex expression in a new ENU mouse model for XLH disease","volume":"13","author":"El Hakam","year":"2022","journal-title":"Genes (Basel)"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2007.01.017","article-title":"Mineralized tissue cells are a principal source of FGF23","volume":"40","author":"Yoshiko","year":"2007","journal-title":"Bone"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C500457200","article-title":"Regulation of fibroblast growth factor-23 signaling by klotho","volume":"281","author":"Kurosu","year":"2006","journal-title":"J Biol Chem"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/nature05315","article-title":"Klotho converts canonical FGF receptor into a specific receptor for FGF23","volume":"444","author":"Urakawa","year":"2006","journal-title":"Nature"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1359\/JBMR.0301264","article-title":"FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis","volume":"19","author":"Shimada","year":"2004","journal-title":"J Bone Miner Res"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1210\/en.2003-1768","article-title":"Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis","volume":"145","author":"Larsson","year":"2004","journal-title":"Endocrinology"},{"key":"B27","article-title":"Rickets\/osteomalacia due to tubular dysfunction","volume":"17","author":"Sekine","year":"2007","journal-title":"Clin Calcium"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.008391","article-title":"Molecular regulation of matrix extracellular phosphoglycoprotein expression by bone morphogenetic protein-2","volume":"284","author":"Cho","year":"2009","journal-title":"J Biol Chem"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/s00223-009-9313-z","article-title":"MEPE\u2019s diverse effects on mineralization","volume":"86","author":"Boskey","year":"2010","journal-title":"Calcif Tissue Int"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1172\/JCI18563","article-title":"Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent","volume":"112","author":"Berndt","year":"2003","journal-title":"J Clin Invest"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfm535","article-title":"Matrix extracellular phosphoglycoprotein causes phosphaturia in rats by inhibiting tubular phosphate reabsorption","volume":"23","author":"Dobbie","year":"2008","journal-title":"Nephrol Dial Transplant"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1172\/JCI32702","article-title":"Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia","volume":"118","author":"Yuan","year":"2008","journal-title":"J Clin Invest"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1677\/joe.1.05989","article-title":"Serum MEPE-ASARM-peptides are elevated in X-linked rickets (HYP): implications for phosphaturia and rickets","volume":"183","author":"Bresler","year":"2004","journal-title":"J Endocrinol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2003.09.004","article-title":"Effect of gene dose and parental origin on bone histomorphometry in X-linked Hyp mice","volume":"34","author":"Qiu","year":"2004","journal-title":"Bone"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1251718\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,5]],"date-time":"2023-12-05T05:13:45Z","timestamp":1701753225000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1251718\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,5]]},"references-count":34,"alternative-id":["10.3389\/fendo.2023.1251718"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2023.1251718","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,5]]},"article-number":"1251718"}}