The X chromosome deletion in &lt;i&gt;Hyp&lt;/i&gt; mice extends into the intergenic region but does not include the &lt;i&gt;Sat&lt;/i&gt; gene downstream from &lt;i&gt;Phex&lt;/i&gt;

Sabbagh, Yves; Gauthier, Claude; Tenenhouse, Harriet S.

doi:10.1159/000071613

Cited by 11 publications

(12 citation statements)

References 37 publications

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“…3). Mean ABR threshold differences between mutants and controls were 48 dB for Hyp-Duk (t-test p < 0.0001), 20 (Fig. 3).…”

Section: Auditory Brainstem Response (Abr) Analysis and Ear Pathologymentioning

confidence: 92%

“…The two HindIII fragments corresponding to exon 13 (6.4 kb) and exon 14 (2.8 kb) were deleted in Hyp-Duk/Y DNA (Fig. 6) The original Hyp mutation involves a deletion of the Phex gene starting in intron 15 and extending through the 3′ region and ~10 kb beyond, but does not include the next downstream gene Sat (Sabbagh et al 2002). We found that the deletion breakpoints for Hyp-2J are in introns 14 and 15 of the Phex gene and that those for Hyp-Duk are in intron 12 and intron 14 (Fig.…”

Section: Molecular Analysis Of the Hyp-duk Mutationmentioning

confidence: 99%

“…The Hyp mutation is a spontaneous deletion that begins in exon 15 and extends through exons [16][17][18][19][20][21][22] (Strom et al 1997) into downstream intergenic sequences (Sabbagh et al 2002). The Ska1 mutation is a chemically induced point mutation in a splice donor site immediately following exon 8 (Carpinelli et al 2002).…”

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New intragenic deletions in the Phex gene clarify X-linked hypophosphatemia-related abnormalities in mice

et al. 2004

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X-linked hypophosphatemic rickets (XLH) in humans is caused by mutations in the PHEX gene. Previously, three mutations in the mouse Phex gene have been reported: Phex Hyp , Gy, and Phex Ska1 . Here we report analysis of two new spontaneous mutations in the mouse Phex gene, Phex and Phex Hyp-Duk . Phex and Phex Hyp-Duk involve intragenic deletions of at least 7.3 kb containing exon 15, and 30 kb containing exons 13 and 14, respectively. Both mutations cause similar phenotypes in males, including shortened hind legs and tail, a shortened square trunk, hypophosphatemia, hypocalcemia, and rachitic bone disease. In addition, mice carrying the Phex Hyp-Duk mutation exhibit background-dependent variable expression of deafness, circling behavior, and cranial dysmorphology, demonstrating the influence of modifying genes on Phexrelated phenotypes. Cochlear cross-sections from Phex Hyp-2J /Y and Phex Hyp-Duk /Y males reveal a thickening of the temporal bone surrounding the cochlea with the presence of a precipitate in the scala tympani. Evidence of the degeneration of the organ of Corti and spiral ganglion also are present in the hearing-impaired Phex Hyp-Duk /Y mice, but not in the normal-hearing Phex Hyp-2J /Y mice. Analysis of the phenotypes noted in Phex Hyp-Duk /Y an Phex Hyp-2J /Y males, together with those noted in Phex Ska1 /Y and Phex Hyp /Y males, now allow XLH-related phenotypes to be separated from non-XLH-related phenotypes, such as those noted in Gy/Y males. Also, identification of the genetic modifiers of hearing and craniofacial dysmorphology in Phex Hyp-Duk / Y mice could provide insight into the phenotypic variation of XLH in humans.X-linked dominant hypophosphatemia (XLH) is the most frequently occurring familial form of hypophosphatemic rickets in humans with an incidence of 1 per 20,000 individuals (Burnett et al. 1964;Tenenhouse 1999 NIH-PA Author ManuscriptThe Hyp mutation is a spontaneous deletion that begins in exon 15 and extends through exons 16-22 (Strom et al. 1997) into downstream intergenic sequences (Sabbagh et al. 2002). The Ska1 mutation is a chemically induced point mutation in a splice donor site immediately following exon 8 (Carpinelli et al. 2002). The Gy mutation is a radiationinduced deletion that removes 160-190 kb, including exons 1-3 and the Sms (spermine synthase) gene (Lorenz et al. 1998;Strom et al. 1997). Given that the gyro deletion includes more than one gene, the previous allelic symbol Phex Gy is inadequate; this mutation is here renamed gyro deletion region, symbol Gy (Mouse Genome Database, http://www.informatics.jax.org). Because neither the Hyp nor Gy mutations is restricted to the Phex coding sequence, it has been problematic to assign a specific phenotype solely to the Phex gene.Here we report the identification of two new spontaneous intragenic deletions in the mouse Phex gene, hypophosphatemia-2 Jackson, symbolized Phex Hyp-2J (Hyp-2J) and hypophosphatemia-Duke, symbolized, Phex Hyp-Duk (Hyp-Duk). Mice carrying either mutation, together with those car...

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“…3). Mean ABR threshold differences between mutants and controls were 48 dB for Hyp-Duk (t-test p < 0.0001), 20 (Fig. 3).…”

Section: Auditory Brainstem Response (Abr) Analysis and Ear Pathologymentioning

confidence: 92%

Section: Molecular Analysis Of the Hyp-duk Mutationmentioning

confidence: 99%

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New intragenic deletions in the Phex gene clarify X-linked hypophosphatemia-related abnormalities in mice

et al. 2004

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“…All of these previously reported mouse mutations result in exon deletion or truncated translation, whereas there are no examples of point mutation leading to single amino acid substitution. The Hyp mutation is a spontaneous deletion that includes intron 15 through exons 16-22 [14] and downstream intergenic sequences [34]. The Gy mutation is a radiation-induced deletion that removes 160-190 kb, including exons 1-3 and the Sms(spermine synthase) gene [14,35].…”

Section: Discussionmentioning

confidence: 99%

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

Xiong

et al. 2007

J Biomed Sci

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N-ethyl-N-nitrosourea (ENU) mutagenesis is a phenotype-driven approach with potential to assign function to every locus in the mouse genome. In this article, we describe a new mutation, Pug, as a mouse model for X-linked hypophosphatemic rickets (XLH) in human. Mice carrying the Pug mutation exhibit abnormal phenotypes including growth retardation, hypophosphatemia and decreased bone mineral density (BMD). The new mutation was mapped to X-chromosome between 65.4 cM and 66.6 cM, where Phex gene resides. Sequence analysis revealed a unique T-to-C transition mutation resulting in Phe-to-Ser substitution at amino acid 80 of PHEX protein. In vitro studies of Pug mutation demonstrated that PHEX(pug) was incompletely glycosylated and sequestrated in the endoplasmic reticulum region of cell, whereas wild-type PHEX could be fully glycosylated and transported to the plasma membrane to exert its function as an endopeptidase. Taken together, the Pug mutant directly confirms the role of Phex in phosphate homeostasis and normal skeletal development and may serves as a new disease model of human hypophosphatemic rickets.

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“…Later studies showed that the Phex mRNA lacked exons 16 to 22, due to a deletion that had one breakpoint in intron 15 and another in the region to the 3’ of the gene [4][5]. The most comprehensive mapping of the deletion was performed by Sabbagh et al who used PCR to refine the location of the breakpoint in intron 15 and determined the other was approximately 10 kb downstream of Phex , consistent with a deletion of between 53 and 58 kb [6]. Despite this, they were unable to amplify a product containing the deletion breakpoints and so the precise extent of the deletion remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

Molecular characterisation of the Hyp deletion and an improved assay for its detection

Sheen

Pilarowski

Wang

et al. 2012

Bone

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The Hyp mouse is a commonly used model for the study of the phosphate wasting disease X-linked hypophosphataemia. The defect in this mouse line is a deletion that includes exons 16 to 22 of Phex, although the exact extent of this X chromosome deletion remains unknown. This complicates genotyping which increases costs, time and difficulty of working with this important model. We aimed to determine the molecular breakpoints of this deletion in order develop a robust assay for its detection. We designed short mapping PCRs around the Phex locus to refine the putative breakpoint locations, then used gap PCR to amplify a product containing the breakpoint junction. DNA sequencing showed the deleted region was approximately 297 kb, significantly larger than previous reports, but did not contain any genes other than Phex. DNA sequence analysis revealed that this deletion may be the result of microhomology-mediated end joining. Finally, we designed a multiplex PCR assay for genotyping Hyp colonies and validated it using a panel of Hyp colony mice. This study provides confirmation of the Hyp phenotype as a single gene defect, a potential mechanism for its formation and an improved method for genotyping that will make working with this strain significantly easier.

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The X chromosome deletion in <i>Hyp</i> mice extends into the intergenic region but does not include the <i>Sat</i> gene downstream from <i>Phex</i>

Cited by 11 publications

References 37 publications

New intragenic deletions in the Phex gene clarify X-linked hypophosphatemia-related abnormalities in mice

New intragenic deletions in the Phex gene clarify X-linked hypophosphatemia-related abnormalities in mice

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

Molecular characterisation of the Hyp deletion and an improved assay for its detection

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