A novel Phex mutation with defective glycosylation causes hypophosphatemia and rickets in mice

Xiong, Xiwen; Qi, Xin; Ge, Xiaomei; Gu, Pengyu; Zhao, Jing; Zhao, Qingshun; Gao, Xiang

doi:10.1007/s11373-007-9199-6

Cited by 14 publications

(11 citation statements)

References 43 publications

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“…Despite the large number of existing mouse models for XLHR, there are still open questions on the mechanism of PHEX in renal phosphate wasting, abnormal vitamin D metabolism, and matrix mineralization (Addison et al 2010; Brownstein et al 2010). The C3HeB/FeJ-Phex BAP012 and C3HeB/FeJ-Phex BAP024 mutant lines represent two new mutant mouse lines with novel point mutations modeling XLHR in addition to previously published models (Carpinelli et al 2002; Lorenz-Depiereux et al 2004; Xiong et al 2008). …”

Section: Discussionmentioning

confidence: 99%

New mouse models for metabolic bone diseases generated by genome-wide ENU mutagenesis

et al. 2012

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Metabolic bone disorders arise as primary diseases or may be secondary due to a multitude of organ malfunctions. Animal models are required to understand the molecular mechanisms responsible for the imbalances of bone metabolism in disturbed bone mineralization diseases. Here we present the isolation of mutant mouse models for metabolic bone diseases by phenotyping blood parameters that target bone turnover within the large-scale genome-wide Munich ENU Mutagenesis Project. A screening panel of three clinical parameters, also commonly used as biochemical markers in patients with metabolic bone diseases, was chosen. Total alkaline phosphatase activity and total calcium and inorganic phosphate levels in plasma samples of F1 offspring produced from ENU-mutagenized C3HeB/FeJ male mice were measured. Screening of 9,540 mice led to the identification of 257 phenodeviants of which 190 were tested by genetic confirmation crosses. Seventy-one new dominant mutant lines showing alterations of at least one of the biochemical parameters of interest were confirmed. Fifteen mutations among three genes (Phex, Casr, and Alpl) have been identified by positional-candidate gene approaches and one mutation of the Asgr1 gene, which was identified by next-generation sequencing. All new mutant mouse lines are offered as a resource for the scientific community.

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Section: Discussionmentioning

confidence: 99%

New mouse models for metabolic bone diseases generated by genome-wide ENU mutagenesis

et al. 2012

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“…It was suspected that the distinct bustling behavior and skeletal abnormalities might be controlled by a single gene. Abnormal behavior, such as circling and head tossing and tilting, is a typical sign of inner ear defects in mice [1,2]; and two Hyp models, Gy and Hyp-Duk [34,36], have also been reported to display abnormal behavior. However, deafness and endolymphatic hydrops due to the Phex Hyp-Duk mutation exhibit background-dependent variable expression [35,43]; and in the Gy, alteration of the spermine synthase gene, rather than Phex , is responsible for inner ear defects [44].…”

Section: Discussionmentioning

confidence: 99%

“…To date, six Phex mutant models, Hyp (a 3'-deletion of the Phex gene) [13,14], Gy (partial deletion of both spermine synthase and Phex ) [13,33], Phex(Ska1) (skipping of exon 8) [34], Hyp-J2 (deletion of exon 15) [35], Hyp-Duk (deletion of exons 13 and 14) [35], and Phex(pug) (glycosylation defects due to Phe-to-Ser substitution at a.a. 80 of Phex) [36] have been reported, while over 260 human disease-associated PHEX mutations have been identified [37-41]http://http:/www.phexdb.mcgill.ca. We have now established a dwarfism-like strain of short-tailed mouse, Kbus/Idr, carrying a novel intragenic deletion of the Phex gene.…”

Section: Introductionmentioning

confidence: 99%

Kbus/Idr, a mutant mouse strain with skeletal abnormalities and hypophosphatemia: Identification as an allele of 'Hyp'

et al. 2011

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BackgroundThe endopeptidase encoded by Phex (phosphate-regulating gene with homologies to endopeptidases linked to the X chromosome) is critical for regulation of bone matrix mineralization and phosphate homeostasis. PHEX has been identified from analyses of human X-linked hypophosphatemic rickets and Hyp mutant mouse models. We here demonstrated a newly established dwarfism-like Kbus/Idr mouse line to be a novel Hyp model.MethodsHistopathological and X-ray examination with cross experiments were performed to characterize Kbus/Idr. RT-PCR-based and exon-directed PCR screening performed to identify the presence of genetic alteration. Biochemical assays were also performed to evaluate activity of alkaline phosphatase.ResultsKbus/Idr, characterized by bone mineralization defects, was found to be inherited in an X chromosome-linked dominant manner. RT-PCR experiments showed that a novel mutation spanning exon 16 and 18 causing hypophosphatemic rickets. Alkaline phosphatase activity, as an osteoblast marker, demonstrated raised levels in the bone marrow of Kbus/Idr independent of the age.ConclusionsKbus mice should serve as a useful research tool exploring molecular mechanisms underlying aberrant Phex-associated pathophysiological phenomena.

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“…PUG mice, with a missense mutation on Phex, were reported as a mouse model of XLH [33]. To confirm the phenotype, we studied the growth sta-tus and skeletal development in PUG firstly.…”

Section: Pug Mice Show Deficient Skeletal Morphology and Abnormal Minmentioning

confidence: 99%

Glucose metabolic abnormality is associated with defective mineral homeostasis in skeletal disorder mouse model

Zou

Xiong

Lai

et al. 2015

Sci. China Life Sci.

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Bone was reported as a crucial organ for regulating glucose homeostasis. In this study, we found that Phex mutant mice (PUG), a model of human X-linked hypophosphatemic rickets (XLH), displayed metabolic abnormality in addition to abnormal phosphate homeostasis, skeletal deformity and growth retardation. Glucose tolerance was elevated with enhanced insulin sensitivity in PUG, though circulating insulin level decreased. Interestingly, bone mineral density defects and glucose metabolic abnormality were both rescued by adding phosphorus-and calcium-enriched supplements in daily diet. Serum insulin level, glucose tolerance and insulin sensitivity showed no differences between PUG and wild-type mice with rescued osteocalcin (OCN) following treatment. Our study suggested that OCN is a potential mediator between mineral homeostasis and glucose metabolism. This investigation brings a new perspective on glucose metabolism regulation through skeleton triggered mineral homeostasis and provides new clues in clinical therapeutics of potential metabolic disorders in XLH patients. glucose metabolism, mineral homeostasis, bone, Phex, X-linked hypophosphatemic rickets Citation:Zou JH, Xiong XW, Lai BB, Sun M, Tu X, Gao X. Glucose metabolic abnormality is associated with defective mineral homeostasis in skeletal disorder mouse model. [5,6]. In the past decades, bone was studied as an endocrinal organ [7,8]. Interactions between bone and energy metabolism aroused extensive interests and concerns [911]. Phex is mainly expressed in osteoblasts and odontoblasts [1214] and its mutations lead to reduced 1,25-(OH) 2 D 3 and elevated circulating FGF23 (fibroblast growth factor 23) [1517]. 1,25-(OH) 2 D 3 and its receptor could influence expression of uncoupling protein (UCP) in adipocytes [18,19]. In vitro studies demonstrate that the role of 1,25-(OH) 2 D 3 in lipid metabolism is regulator of peroxisome proliferator-activated receptor alpha (Ppara) [20]. Circulating FGF23 is also associated with fat mass and serum lipids [21]. In mouse models of XLH, like Hyp mice, decreased renal glucose reabsorption activity [22], increased glucose production in renal proximal tubules [23] and osteoblasts [24] were observed. The only known physiological substrate of PHEX protein, acidic serine aspartate-rich MEPE associated motif (ASARM peptide), could regulate glucose metabolism and insulin signaling [14]. The above findings indicate PHEXmediated association between skeletal function and energy

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A novel Phex mutation with defective glycosylation causes hypophosphatemia and rickets in mice

Cited by 14 publications

References 43 publications

New mouse models for metabolic bone diseases generated by genome-wide ENU mutagenesis

New mouse models for metabolic bone diseases generated by genome-wide ENU mutagenesis

Kbus/Idr, a mutant mouse strain with skeletal abnormalities and hypophosphatemia: Identification as an allele of 'Hyp'

Glucose metabolic abnormality is associated with defective mineral homeostasis in skeletal disorder mouse model

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