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Agnès Linglart - One of the best experts on this subject based on the ideXlab platform.
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Diagnosis, treatment-monitoring and follow-up of children and adolescents with X-Linked Hypophosphatemia (XLH).
Metabolism, 2020Co-Authors: Anya Rothenbuhler, Wolfgang Högler, Dirk Schnabel, Agnès LinglartAbstract:Early diagnosis, optimal therapeutic management and regular follow up of children with X-Linked Hypophosphatemia (XLH) determine their long term outcomes and future quality of life. Biochemical screening of potentially affected newborns in familial cases and improving physician's knowledge on clinical signs, symptoms and biochemical characteristics of XLH for de novo cases should lead to earlier diagnosis and treatment initiation. The follow-up of children with XLH includes clinical, biochemical and radiological monitoring of treatment (efficacy and complications) and screening for XLH-related dental, neurosurgical, rheumatological, cardiovascular, renal and ENT complications. In 2018, the European Union approved the use of burosumab, a humanized monoclonal anti-FGF23 antibody, as an alternative therapy to conventional therapy (active vitamin D analogues and phosphate supplements) in growing children with XLH and insufficiently controlled disease. Diagnostic criteria of XLH and the principles of disease management with conventional treatment or with burosumab are reviewed in this paper.
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On X-Linked Hypophosphatemia at the European society of pediatric endocrinology meeting, Vienna, Austria; september 19–21, 2019
Ibnosina Journal of Medicine and Biomedical Sciences, 2020Co-Authors: Hussain Alsaffar, Senthil Senniappan, Agnès LinglartAbstract:X-Linked Hypophosphatemia (XLH) is the most common form of inherited hypophosphatemic rickets. Phosphate wasting results in weak, soft and deformed bones, impaired growth, and affected mobility. It is mainly caused by a loss of function mutation in PHEX gene that leads to elevated fibroblast growth factor-23 which mediates the phosphate wasting. During the 58th annual meeting of the European Society of Pediatric Endocrinology (ESPE) held in Vienna between September 19, 2019 and 21, 2019, nearly 100 free communications and a dedicated symposium focused on XLH. The authors attended the conference and wished to share its highlights pertaining to XLH and burosumab therapy to extend the benefit to other professionals who did not attend.
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Management of X-Linked Hypophosphatemia in adults.
Metabolism: clinical and experimental, 2019Co-Authors: Anne-lise Lecoq, Agnès Linglart, Maria Luisa Brandi, Peter KamenickýAbstract:X-Linked Hypophosphatemia (XLH) is caused by mutations in the PHEX gene which result in Fibroblast Growth Factor-23 (FG-F23) excess and phosphate wasting. Clinically, XLH children present with rickets, bone deformities and short stature. In adulthood, patients may still be symptomatic with bone and joint pain, osteomalacia-related fractures or pseudofractures, precocious osteoarthrosis, enthesopathy, muscle weakness and severe dental anomalies. Besides these musculoskeletal and dental manifestations, adult XLH patients are also prone to secondary and tertiary hyperparathyroidism, cardiovascular and metabolic disorders. Pathophysiology of hyperparathyroidism is only partially understood but FGF23 excess and deficient production of calcitriol likely contributes to its development. Similarly, the pathophysiological mechanisms of potential cardiovascular and metabolic involvements are not clear, but FGF-23 excess may play an essential role. Treatment should be considered in symptomatic patients, patients undergoing orthopedic or dental surgery and women during pregnancy and lactation. Treatment with oral phosphate salts and active vitamin D analogs has incomplete efficacy and potential risks. Burosumab, a recombinant human monoclonal antibody against FGF-23, has proven its efficacy in phase 2 and phase 3 clinical trials in adult patients with XLH, but currently its position as first line or second line treatment differ among the countries.
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X-Linked Hypophosphatemia: Management and treatment prospects.
Joint bone spine, 2019Co-Authors: Anne-sophie Lambert, Volha V. Zhukouskaya, Anya Rothenbuhler, Agnès LinglartAbstract:Abstract X-Linked Hypophosphatemia (XLH), due to a PHEX gene mutation, is the most common genetic form of rickets and osteomalacia. Manifestations in children consist of rickets, lower-limb bone deformities, bone pain, failure to thrive, dental abscesses, and/or craniostenosis. Adults may present with persistent bone pain, early osteoarthritis, hairline fractures and Looser zones, enthesopathy, and/or periodontitis. Regardless of whether the patient is an infant, child, adolescent or adult, an early diagnosis followed by optimal treatment is crucial to control the clinical manifestations, prevent complications, and improve quality of life. Treatment options include active vitamin D analogs and phosphate supplementation to correct the 1.25(OH)2 vitamin D deficiency and to compensate for the renal phosphate wasting, respectively. The recently introduced FGF23 antagonist burosumab is designed to restore renal phosphate reabsorption by the proximal tubule and to stimulate endogenous calcitriol production. In Europe, burosumab is licensed for use in pediatric patients older than 1 year who have XLH. This review discusses the diagnosis and treatment of XLH and describes the indications of the various available treatments.
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Burosumab Therapy in Children with X-Linked Hypophosphatemia.
The New England journal of medicine, 2018Co-Authors: Thomas O. Carpenter, Michael P. Whyte, Erik A. Imel, Annemieke Boot, Wolfgang Högler, Agnès Linglart, Raja Padidela, William Van’t Hoff, Meng Mao, Chao-yin ChenAbstract:Abstract Background X-Linked Hypophosphatemia is characterized by increased secretion of fibroblast growth factor 23 (FGF-23), which leads to Hypophosphatemia and consequently rickets, osteomalacia...
Zhanjun Li - One of the best experts on this subject based on the ideXlab platform.
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crispr cas9 mediated mutation of phex in rabbit recapitulates human x linked Hypophosphatemia xlh
Human Molecular Genetics, 2016Co-Authors: Lin Yuan, Jichao Deng, Yong Wang, Mao Chen, Zhanjun LiAbstract:Abstract X-Linked Hypophosphatemia (XLH) is the most common cause of inheritable rickets, with an incidence of 1/20 000 in humans. Inactivation or mutation of the gene PHEX, a phosphate-regulating endopeptidase, leads to Hypophosphatemia and defective bone mineralization in XLH patients. Presently, there is no adequate animal model for safety assessments of physiotherapies and drug screening for XLH rickets. In this study, an XLH model was generated via PHEX gene knockout (KO) through coinjection of clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9)/sgRNA mRNA into rabbit zygotes. The typical phenotypes of growth retardation, Hypophosphatemia, elevated serum FGF23 and bone mineralization were observed in the PHEX KO rabbits but not in normal controls. In summary, for the first time, we have successfully obtained PHEX KO rabbits and recapitulated human XLH using the CRISPR/Cas9 system. This novel XLH rabbit model could be utilized as a drug screening model for XLH prevention and preclinical therapy.
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CRISPR/Cas9-mediated mutation of PHEX in rabbit recapitulates human X-Linked Hypophosphatemia (XLH)
Human Molecular Genetics, 2016Co-Authors: Lin Yuan, Jichao Deng, Yong Wang, Mao Chen, Zhanjun LiAbstract:Abstract X-Linked Hypophosphatemia (XLH) is the most common cause of inheritable rickets, with an incidence of 1/20 000 in humans. Inactivation or mutation of the gene PHEX, a phosphate-regulating endopeptidase, leads to Hypophosphatemia and defective bone mineralization in XLH patients. Presently, there is no adequate animal model for safety assessments of physiotherapies and drug screening for XLH rickets. In this study, an XLH model was generated via PHEX gene knockout (KO) through coinjection of clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9)/sgRNA mRNA into rabbit zygotes. The typical phenotypes of growth retardation, Hypophosphatemia, elevated serum FGF23 and bone mineralization were observed in the PHEX KO rabbits but not in normal controls. In summary, for the first time, we have successfully obtained PHEX KO rabbits and recapitulated human XLH using the CRISPR/Cas9 system. This novel XLH rabbit model could be utilized as a drug screening model for XLH prevention and preclinical therapy.
Michael P. Whyte - One of the best experts on this subject based on the ideXlab platform.
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Growth Curves for Children with X-Linked Hypophosphatemia
The Journal of clinical endocrinology and metabolism, 2020Co-Authors: Meng Mao, Michael P. Whyte, Thomas O. Carpenter, Chao-yin Chen, Alison Skrinar, Javier San Martin, Alan D. RogolAbstract:CONTEXT We characterized linear growth in infants and children with X-Linked Hypophosphatemia (XLH). OBJECTIVE Provide linear growth curves for children with XLH from birth to early adolescence. DESIGN Data from 4 prior studies of XLH were pooled to construct growth curves. UX023-CL002 was an observational, retrospective chart review. Pretreatment data were collected from 3 interventional trials: two phase 2 trials (UX023-CL201, UX023-CL205) and a phase 3 trial (UX023-CL301). SETTING Medical centers with expertise in treating XLH. PATIENTS Children with XLH, 1-14 years of age. INTERVENTION None. MAIN OUTCOME MEASURE Height-for-age linear growth curves, including values for the 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles for children with XLH compared to population norms. RESULTS A total of 228 patients (132 girls, 96 boys) with 2381 height measurements were included. Nearly all subjects (> 99%) reported prior management with supplementation therapy. Compared to the Center for Disease Control and Prevention growth curves, boys at age 3 months, 6 months, 9 months, 1 year, and 2 years had median height percentiles of 46%, 37%, 26%, 18%, and 5%, respectively; for girls the median height percentiles were 52%, 37%, 25%, 18%, and 7%, respectively. Annual growth in children with XLH fell below that of healthy children near 1 year of age and progressively declined during early childhood, with all median height percentiles < 8% between 2 and 12 years old. CONCLUSION Children with XLH show decreased height gain by 1 year of age and remain below population norms thereafter. These data will help evaluate therapeutic interventions on linear growth for pediatric XLH.
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Burosumab Therapy in Children with X-Linked Hypophosphatemia.
The New England journal of medicine, 2018Co-Authors: Thomas O. Carpenter, Michael P. Whyte, Erik A. Imel, Annemieke Boot, Wolfgang Högler, Agnès Linglart, Raja Padidela, William Van’t Hoff, Meng Mao, Chao-yin ChenAbstract:Abstract Background X-Linked Hypophosphatemia is characterized by increased secretion of fibroblast growth factor 23 (FGF-23), which leads to Hypophosphatemia and consequently rickets, osteomalacia...
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Osteopontin and the dento-osseous pathobiology of X-Linked Hypophosphatemia.
Bone, 2016Co-Authors: Tchilalo Boukpessi, Francis H. Glorieux, Michael P. Whyte, Agnès Linglart, Benjamin R. Coyac, Betty Hoac, Thibaut Léger, Camille Garcia, Philippe Wicart, Catherine ChaussainAbstract:Abstract Seven young patients with X-Linked Hypophosphatemia (XLH, having inactivating PHEX mutations) were discovered to accumulate osteopontin (OPN) at the sites of defective bone mineralization near osteocytes − the so-called hallmark periosteocytic (lacunar) “halos” of XLH. OPN was also localized in the pericanalicular matrix extending beyond the osteocyte lacunae, as well as in the hypomineralized matrix of tooth dentin. OPN, a potent inhibitor of mineralization normally degraded by PHEX , is a member of a family of acidic, phosphorylated, calcium-binding, extracellular matrix proteins known to regulate dental, skeletal, and pathologic mineralization. Associated with the increased amount of OPN (along with inhibitory OPN peptide fragments) in XLH bone matrix, we found an enlarged, hypomineralized, lacuno-canalicular network – a defective pattern of skeletal mineralization that decreases stiffness locally at: i ) the cell-matrix interface in the pericellular environment of the mechanosensing osteocyte, and ii ) the osteocyte's dendritic network of cell processes extending throughout the bone. Our findings of an excess of inhibitory OPN near osteocytes and their cell processes, and in dentin, spatially correlates with the defective mineralization observed at these sites in the skeleton and teeth of XLH patients. These changes likely contribute to the dento-osseous pathobiology of XLH, and participate in the aberrant bone adaptation and remodeling seen in XLH.
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X-Linked Hypophosphatemia attributable to pseudoexons of the PHEX gene.
The Journal of clinical endocrinology and metabolism, 2001Co-Authors: Paul T. Christie, Brian Harding, M. Andrew Nesbit, Michael P. Whyte, Rajesh V. ThakkerAbstract:X-Linked Hypophosphatemia is commonly caused by mutations of the coding region of PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). However, such PHEX mutations are not detected in approximately one third of X-Linked Hypophosphatemia patients who may harbor defects in the noncoding or intronic regions. We have therefore investigated 11 unrelated X-Linked Hypophosphatemia patients in whom coding region mutations had been excluded, for intronic mutations that may lead to mRNA splicing abnormalities, by the use of lymphoblastoid RNA and RT-PCRs. One X-Linked Hypophosphatemia patient was found to have 3 abnormally large transcripts, resulting from 51-bp, 100-bp, and 170-bp insertions, all of which would lead to missense peptides and premature termination codons. The origin of these transcripts was a mutation (g to t )a t position 1268 of intron 7, which resulted in the occurrence of a high quality novel donor splice site (ggaagg to gtaagg). Splicing between this novel donor splice site and 3 preexisting, but normally silent, acceptor splice sites within intron 7 resulted in the occurrences of the 3 pseudoexons. This represents the first report of PHEX pseudoexons and reveals further the diversity of genetic abnormalities causing X-Linked Hypophosphatemia. (J Clin Endocrinol Metab 86: 3840 –3844, 2001)
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x linked Hypophosphatemia attributable to pseudoexons of the phex gene
The Journal of Clinical Endocrinology and Metabolism, 2001Co-Authors: Paul T. Christie, Brian Harding, Michael P. Whyte, Andrew M Nesbit, Rajesh V. ThakkerAbstract:X-Linked Hypophosphatemia is commonly caused by mutations of the coding region of PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). However, such PHEX mutations are not detected in approximately one third of X-Linked Hypophosphatemia patients who may harbor defects in the noncoding or intronic regions. We have therefore investigated 11 unrelated X-Linked Hypophosphatemia patients in whom coding region mutations had been excluded, for intronic mutations that may lead to mRNA splicing abnormalities, by the use of lymphoblastoid RNA and RT-PCRs. One X-Linked Hypophosphatemia patient was found to have 3 abnormally large transcripts, resulting from 51-bp, 100-bp, and 170-bp insertions, all of which would lead to missense peptides and premature termination codons. The origin of these transcripts was a mutation (g to t) at position+ 1268 of intron 7, which resulted in the occurrence of a high quality novel donor splice site (ggaagg to gtaagg). Splicing between this novel don...
Michel Baum - One of the best experts on this subject based on the ideXlab platform.
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Role of prostaglandins in the pathogenesis of X-Linked Hypophosphatemia
Pediatric Nephrology, 2006Co-Authors: Michel Baum, Ashu Syal, Raymond Quigley, Mouin SeikalyAbstract:X-Linked Hypophosphatemia is an X-Linked dominant disorder resulting from a mutation in the PHEX gene. PHEX stands for ph osphate-regulating gene with e ndopeptidase activity, which is located on the X chromosome. Patients with X-Linked Hypophosphatemia have Hypophosphatemia due to renal phosphate wasting and low or inappropriately normal levels of 1,25-dihydroxyvitamin D. The renal phosphate wasting is not intrinsic to the kidney but likely due to an increase in serum levels of fibroblast growth factor-23 (FGF-23), and perhaps other phosphate-wasting peptides previously known as phosphatonins. Patients with X-Linked Hypophosphatemia have short stature, rickets, bone pain and dental abscesses. Current therapy is oral phosphate and vitamin D which effectively treats the rickets and bone pain but does not adequately improve short stature. In this review, we describe recent observations using Hyp mice; mice with the same mutation as patients with X-Linked Hypophosphatemia. We have recently found that Hyp mice have abnormal renal prostaglandin production, which may be an important factor in the pathogenesis of this disorder. Administration of FGF-23 in vivo results in phosphaturia and an increase in prostaglandin excretion, and FGF-23 increases proximal tubule prostaglandin production in vitro. In Hyp mice, indomethacin improves the phosphate transport defect in vitro and in vivo. Whether indomethacin has the same effect in patients with X-Linked Hypophosphatemia is unknown.
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Thiazide Diuretics Arrest the Progression of Nephrocalcinosis in Children With X-Linked Hypophosphatemia
Pediatrics, 2001Co-Authors: Mouin G. Seikaly, Michel BaumAbstract:Objective. X-Linked Hypophosphatemia (XLH) is characterized clinically by rickets, Hypophosphatemia, and hyperphosphaturia. Conventional treatment of XLH with oral phosphate and vitamin D is associated with increased urinary calcium excretion and nephrocalcinosis. Thiazide diuretics decrease urinary calcium excretion. The objective of this study was to determine the effect of thiazide diuretics on the clinical and radiologic course of nephrocalcinosis in children with XLH. Methods. The effect of hydrochlorothiazide (HCTZ) on clinical and radiologic progression of nephrocalcinosis was evaluated in 11 children with XLH. All patients had been treated previously with vitamin D and oral phosphate and had radiologic evidence of nephrocalcinosis. The average age of the patients at the start of HCTZ was 6.6 ± 1.0 years. The effect of oral HCTZ at 0.8 ± 0.1 mg/kg body weight per day given for 3.3 ± 0.6 years on the progression of nephrocalcinosis and urinary calcium excretion was evaluated. Results. There was no change in serum phosphorous, calcium, potassium, and chloride after HCTZ therapy. HCTZ therapy increased serum bicarbonate and decreased urinary calcium excretion. The grade of nephrocalcinosis increased from 0.4 ± 0.2 to 1.5 ± 0.3 in the 2.3 ± 0.3 years before initiation of HCTZ therapy, whereas the degree of nephrocalcinosis was stable after 3.3 ± 0.6 years of HCTZ therapy (1.5 ± 0.3 vs 3.0 ± 0.3). Conclusion. HCTZ decreased urinary calcium excretion but did not result in the resolution of nephrocalcinosis. However, when compared with the control period, HCTZ prevented the progression of nephrocalcinosis in children with XLH.
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Effect of dipyridamole on serum and urinary phosphate in X-Linked Hypophosphatemia.
Pediatric Nephrology, 2000Co-Authors: Mouin G. Seikaly, Raymond Quigley, Michel BaumAbstract:X-Linked Hypophosphatemia (XLH) is characterized clinically by rickets, Hypophosphatemia and hyperphosphaturia. Conventional treatment of XLH with oral phosphate and vitamin D is associated with hypercalcuria and nephrocalcinosis. Recently, intravenous and oral dipyridamole has been reported to decrease fractional excretion of phosphate in adults with idiopathic hyperphosphaturia. Our objective was to determine whether oral dipyridamole therapy reduces urinary phosphate excretion and increases serum phosphate concentration in children with XLH. A prospective study was performed in six children with XLH. The average age of the patients at the start of the study was 12.5±1.0 years. The effects of 12 weeks of oral dipyridamole therapy, at 4.4±0.4 mg/kg body weight per day, on serum phosphorous, parathyroid hormone (PTH), 1,25 (OH)2 vitamin D, osteocalcin, tubular maximum for phosphate reabsorption (TmP/GFR), urinary calcium excretion, and cyclic adenosine 3’,5’-monophosphate (cAMP) excretion, were compared to baseline levels. Our results show that there was no change in serum phosphorous concentration or TmP/GFR after 12 weeks of dipyridamole therapy. Dipyridamole therapy also had no effect on serum PTH, serum 1,25 (OH)2 vitamin D, alkaline phosphatase, osteocalcin levels, urinary calcium or cAMP excretion. We therefore concluded that in children with XLH, a 12-week course of dipyridamole had no effect on serum phosphorous or its urinary excretion. Dipyridamole therapy is unlikely to improve the bone disease in children with XLH.
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Nephrocalcinosis is associated with renal tubular acidosis in children with X-Linked Hypophosphatemia.
Pediatrics, 1996Co-Authors: Mouin G. Seikaly, Richard H. Browne, Michel BaumAbstract:BACKGROUND: X-Linked Hypophosphatemia is characterized clinically by rickets and growth retardation. Therapy of this disorder with phosphate and vitamin D often produces nephrocalcinosis. The long-term effects of nephrocalcinosis on renal function in patients with X-Linked Hypophosphatemia are unknown. The purpose of this study was to evaluate the prevalence of glomerular and tubular disorders in patients with X-Linked Hypophosphatemia who developed nephrocalcinosis. METHODS: The creatinine clearance and the prevalence of renal tubular acidosis were compared in 19 patients with X-Linked Hypophosphatemia and nephrocalcinosis with 15 patients with X-Linked Hypophosphatemia without nephrocalcinosis. RESULTS: Sixteen of the 19 patients (84%) with nephrocalcinosis had a hyperchloremic metabolic acidosis compared with one of the 13 patients without nephrocalcinosis (P < .01). The serum bicarbonate of patients with nephrocalcinosis was 20.0 +/- 0.7 as compared to 24.5 +/- 0.6 mmol/L in patients without nephrocalcinosis (P < .01). The urinary anion gap was positive in all patients with acidosis (+62.1 +/- 13.3 mmol/L). The creatinine clearance was 125 +/- 6 mL/min/1.73 m2 in patients with nephrocalcinosis and 124 +/- 7 mL/min/1.73 m2 in those without nephrocalcinosis. CONCLUSION: Therapy of X-Linked Hypophosphatemia is often associated with nephrocalcinosis. Nephrocalcinosis is associated with renal tubular acidosis in patients with X-Linked Hypophosphatemia.
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Stimulation of growth hormone secretion in children with X-Linked Hypophosphatemia
Pediatric nephrology (Berlin Germany), 1995Co-Authors: Mouin G. Seikaly, Michel BaumAbstract:X-Linked Hypophosphatemia is characterized by low serum phosphorus, relative vitamin D deficiency and rickets. Despite adequate metabolic control with oral phosphate and vitamin D therapy, patients with X-Linked Hypophosphatemia have short stature. Whether growth hormone (GH) deficiency plays a role in short stature in patients with X-Linked Hypophosphatemia is not known. The purpose of this report was to investigate the response of GH to sequential paired pharmacological stimulation in patients with X-Linked Hypophosphatemia. Basal GH was 3.8±0.7 ng/ml, insulin-like growth factor-I (IGF-I) was 225±38 ng/ml and IGF binding protein-3 was 3.0±0.2 mg/l in 16 children studied with X-Linked Hypophosphatemia. In response tol-dopa and arginine hydrochloride stimulation, serum GH rose to above 7 mg/ml in all patients. Thus, the short stature in patients with X-Linked Hypophosphatemia is not due to a GH/IGF-I secretory defect.
Lin Yuan - One of the best experts on this subject based on the ideXlab platform.
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crispr cas9 mediated mutation of phex in rabbit recapitulates human x linked Hypophosphatemia xlh
Human Molecular Genetics, 2016Co-Authors: Lin Yuan, Jichao Deng, Yong Wang, Mao Chen, Zhanjun LiAbstract:Abstract X-Linked Hypophosphatemia (XLH) is the most common cause of inheritable rickets, with an incidence of 1/20 000 in humans. Inactivation or mutation of the gene PHEX, a phosphate-regulating endopeptidase, leads to Hypophosphatemia and defective bone mineralization in XLH patients. Presently, there is no adequate animal model for safety assessments of physiotherapies and drug screening for XLH rickets. In this study, an XLH model was generated via PHEX gene knockout (KO) through coinjection of clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9)/sgRNA mRNA into rabbit zygotes. The typical phenotypes of growth retardation, Hypophosphatemia, elevated serum FGF23 and bone mineralization were observed in the PHEX KO rabbits but not in normal controls. In summary, for the first time, we have successfully obtained PHEX KO rabbits and recapitulated human XLH using the CRISPR/Cas9 system. This novel XLH rabbit model could be utilized as a drug screening model for XLH prevention and preclinical therapy.
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CRISPR/Cas9-mediated mutation of PHEX in rabbit recapitulates human X-Linked Hypophosphatemia (XLH)
Human Molecular Genetics, 2016Co-Authors: Lin Yuan, Jichao Deng, Yong Wang, Mao Chen, Zhanjun LiAbstract:Abstract X-Linked Hypophosphatemia (XLH) is the most common cause of inheritable rickets, with an incidence of 1/20 000 in humans. Inactivation or mutation of the gene PHEX, a phosphate-regulating endopeptidase, leads to Hypophosphatemia and defective bone mineralization in XLH patients. Presently, there is no adequate animal model for safety assessments of physiotherapies and drug screening for XLH rickets. In this study, an XLH model was generated via PHEX gene knockout (KO) through coinjection of clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9)/sgRNA mRNA into rabbit zygotes. The typical phenotypes of growth retardation, Hypophosphatemia, elevated serum FGF23 and bone mineralization were observed in the PHEX KO rabbits but not in normal controls. In summary, for the first time, we have successfully obtained PHEX KO rabbits and recapitulated human XLH using the CRISPR/Cas9 system. This novel XLH rabbit model could be utilized as a drug screening model for XLH prevention and preclinical therapy.
