The Gy mutation: another cause of X-linked hypophosphatemia in mouse.

Lyon, Mary F.; Scriver, Charles R.; Baker, L. R. I.; Tenenhouse, Harriet S.; Kronick, Jonathan B.; Mandla, S.

doi:10.1073/pnas.83.13.4899

Cited by 118 publications

(120 citation statements)

References 8 publications

(10 reference statements)

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“…Two mouse mutations, Hyp (Eicher et al 1976) and Gy (Lyon et al 1986), map to the syntenic region of the mouse X chromosome, and affected mice exhibit hypophosphatemic rickets. Gy mice have some additional disease features to Hyp mice that include circling behavior, inner ear abnormalities, sterility, and reduced viability.…”

Section: Genome Research 573mentioning

confidence: 99%

“…NEP is known to inactivate a wide variety of peptide hormones, whereas ECE-1 and ECE-2 process inactive big endothelin 1 to its active form. A substrate for PEX has not yet been identified, and hence the role of this endopeptidase in the pathophysiology of HYP is not clear.Two mouse mutations, Hyp (Eicher et al 1976) and Gy (Lyon et al 1986), map to the syntenic region of the mouse X chromosome, and affected mice exhibit hypophosphatemic rickets. Gy mice have some additional disease features to Hyp mice that include circling behavior, inner ear abnormalities, sterility, and reduced viability.…”

mentioning

confidence: 99%

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Genomic Organization of the Human PEX Gene Mutated in X-Linked Dominant Hypophosphatemic Rickets

Francis¹,

Strom²,

Hennig³

et al. 1997

Genome Res.

156

102

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X-linked dominant hypophosphatemic rickets (HYP) is the most common form of hereditary rickets. Recently we have cloned the PEX gene and shown it to be mutated and deleted in HYP individuals. We have now completely sequenced a 243-kb genomic region containing PEX and have identified all intron-exon boundary sequences. We show that PEX, homologous to members of a neutral endopeptidase family, has an exon organization that is very similar to neprilysin. We have performed an extensive mutation analysis examining all 22 PEX coding exons in 29 familial and 14 sporadic cases of hypophosphatemia. Sequence changes include missense, frameshift, nonsense, and splice site mutations and intragenic deletions. A mutation was found in 25 (86%) of the 29 familial cases and 8 (57%) of the 14 sporadic cases. Our data provide the first evidence that most of the familial and also a large number of the sporadic cases of hypophosphatemia are caused by loss-of-function mutations in PEX.[The sequence data described in this paper have been submitted to GenBank under accession nos. Y08111-Y08132 and Y10196.] X-linked dominant hypophosphatemic rickets [HYP; MIM 307800 (Mendelian inheritance in man number); McKusick 1994] has an incidence of 1 in 20,000 individuals and is the most common form of hypophosphatemia. The main physiological traits of the disease are a leak of phosphate from the kidney causing low phosphate levels in the blood and defective bone mineralization. Patients exhibit rickets and osteomalacia, lower extremity deformities, short stature, bone pain, dental abnormalities, and abnormal vitamin D metabolism. Several other less common disorders of inherited renal phosphate wasting also exist, including an autosomal dominant form (ADHR; McKusick 1994, MIM 193100;Econs and McEnery 1997) and hereditary hypophosphatemic rickets with hypercalciuria (HHRH; McKusick 1994, MIM 241530), which shows a complex inheritance pattern (Tieder et al. 1987). An additional tumor-induced form of hypophosphatemia exists, oncogenic hypophosphatemic osteomalacia, in which removal of the tumor leads to a return in normal phosphate levels (Fukomoto et al. 1979;Lobaugh et al. 1984;Weidner et al. 1985). These additional forms of the disease suggest that phosphate homeostasis is a complex process involving multiple gene products.Recently we cloned a candidate gene, PEX, for the X-linked dominant form of hypophosphatemic rickets, localized to the human Xp22 region (HYP GENOME RESEARCH 573Cold Spring Harbor Laboratory Press on May 10, 2018 -Published by genome.cshlp.org Downloaded from Consortium 1995). PEX has homologies to a family of zinc metalloproteases that includes neprilysin (NEP; D' Adamio et al. 1989), the Kell antigen (KELL; Lee et al. 1991) and endothelin-converting enzymes 1 and 2 (ECE-1 and ECE-2; Schmidt et al. 1994;Xu et al. 1994;Emoto and Yanagisawa 1995). NEP is known to inactivate a wide variety of peptide hormones, whereas ECE-1 and ECE-2 process inactive big endothelin 1 to its active form. A substrate for PEX has not yet been ...

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Section: Genome Research 573mentioning

confidence: 99%

mentioning

confidence: 99%

Genomic Organization of the Human PEX Gene Mutated in X-Linked Dominant Hypophosphatemic Rickets

Francis¹,

Strom²,

Hennig³

et al. 1997

Genome Res.

156

102

View full text Add to dashboard Cite

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“…8 Additionally, the Gy mouse has hypophosphatemic rickets and deletion of the 5 0 end of the Phex gene. 9 However, it is unlikely that the deletion of Phex contributes to the neurological findings, since two other mouse models for X-linked hypophosphatemic rickets, the Hyp mouse 10 and the Ska1 mouse, 11 do not have neurological symptoms. Therefore, although little is known about the specific cellular function of spermine, it was hypothesized that the neurological abnormalities found in Gy males were due to the deficiency of spermine.…”

Section: Introductionmentioning

confidence: 99%

X-linked spermine synthase gene (SMS) defect: the first polyamine deficiency syndrome

et al. 2003

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Polyamines (putrescine, spermidine, spermine) are ubiquitous, simple molecules that interact with a variety of other molecules in the cell, including nucleic acids, phospholipids and proteins. Various studies indicate that polyamines are essential for normal cell growth and differentiation. Furthermore, these molecules, especially spermine, have been shown to modulate ion channel activities of certain cells. Nonetheless, little is known about the specific cellular functions of these compounds, and extensive laboratory investigations have failed to identify a heritable condition in humans in which polyamine synthesis is perturbed. We report the first polyamine deficiency syndrome caused by a defect in spermine synthase (SMS). The defect results from a splice mutation, and is associated with the Snyder-Robinson syndrome (SRS, OMIM_309583), an X-linked mental retardation disorder. The affected males have mild-tomoderate mental retardation (MR), hypotonia, cerebellar circuitry dysfunction, facial asymmetry, thin habitus, osteoporosis, kyphoscoliosis, decreased activity of SMS, correspondingly low levels of intracellular spermine in lymphocytes and fibroblasts, and elevated spermidine/spermine ratios. The clinical features observed in SRS are consistent with cerebellar dysfunction and a defective functioning of red nucleus neurons, which, at least in rats, contain high levels of spermine. Additionally, the presence of MR reflects a role for spermine in cognitive function, possibly by spermine's ability to function as an 'intrinsic gateway' molecule for inward rectifier K þ channels.

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“…The Gy mutation is dominantly inherited and is X-linked [22]. Gy males are sterile and exhibit a more severe phenotype than female Gy\X mice.…”

Section: Micementioning

confidence: 99%

“…The gene deletion responsible for the gyro phenotype [22] includes not only the spermine synthase gene but also the Phex gene, which is expressed in calcified tissues (bone and teeth) of normal mice. We therefore chose to isolate skin fibroblasts, which exhibit no significant Phex gene expression [24].…”

Section: Characterization Of Skin Fibroblast Cultures Established Fromentioning

confidence: 99%

Skin fibroblasts from spermine synthase-deficient hemizygous gyro male (Gy/Y) mice overproduce spermidine and exhibit increased resistance to oxidative stress but decreased resistance to UV irradiation

Nilsson

Gritli-Linde

Heby

2000

Biochemical Journal

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Hemizygous gyro male (Gy/Y) mice are a model for X-linked hypophosphataemic rickets. As in humans, the disease is caused by deletions in the Phex gene, a phosphate-regulating gene having homologies with endopeptidases on the X chromosome. Some phenotypic abnormalities in Gy/Y mice have recently been attributed to the fact that the Gy deletion also includes the neighbouring spermine synthase gene, resulting in spermine deficiency. Spermine and its precursors spermidine and putrescine are essential for cell growth and differentiation. As a novel method for studying the function of spermine, we established primary cultures of skin fibroblasts from hemizygous Gy/Y mice. The Gy/Y cells contained no detectable spermine. In view of the fact that spermine is a free-radical scavenger in vitro, we were surprised to find that Gy/Y cells were more resistant to oxidative stress than their normal (X/Y) counterparts. However, our finding that spermidine accumulates markedly in the spermine-deficient Gy/Y cells can probably explain this increased resistance. It is the first indication that spermidine can serve as a free-radical scavenger in vivo and not only in vitro. When subjecting the Gy/Y cells to UV-C irradiation we made another interesting finding: the mutant cells were more sensitive than the normal X/Y cells. This finding indicates that spermine, probably because of its high-affinity binding to DNA, is important in protection against chromatin damage.

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The Gy mutation: another cause of X-linked hypophosphatemia in mouse.

Cited by 118 publications

References 8 publications

Genomic Organization of the Human PEX Gene Mutated in X-Linked Dominant Hypophosphatemic Rickets

Genomic Organization of the Human PEX Gene Mutated in X-Linked Dominant Hypophosphatemic Rickets

X-linked spermine synthase gene (SMS) defect: the first polyamine deficiency syndrome

Skin fibroblasts from spermine synthase-deficient hemizygous gyro male (Gy/Y) mice overproduce spermidine and exhibit increased resistance to oxidative stress but decreased resistance to UV irradiation

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