Spermine deficiency in Gy mice caused by deletion of the spermine synthase gene

Abstract

Two mouse mutations gyro (Gy) and hypophosphatemia (Hyp) are mouse models for X-linked hypophosphatemic rickets and have been shown to be deleted for the 5' and 3' end of the mouse homolog of PHEX (phosphate regulating gene with homologies to endopeptidases on the X chromosome; formerly called PEX), respectively. In addition to the metabolic disorder observed in Hyp mice, male Gy mice are sterile and show circling behavior and reduced viability. The human SMS (spermine synthase) gene maps approximately 39 kb upstream of PHEX and is transcribed in the same direction. To elucidate the complex phenotype of Gy mice, we characterized the genomic region upstream of Phex. By establishing the genomic structure of mouse Sms, a 160-190 kb deletion was shown in Gy mice, which includes both Phex and Sms. There are several pseudogenes of SMS / Sms in man and mouse. Northern analysis revealed three different Sms transcripts which are absent in Gy mice. Measurement of polyamine levels revealed a marked decrease in spermine in liver and pancreas of affected male Gy mice. Analysis of brain tissue revealed no gross or histological abnormalities. Gy provides a mouse model for a defect in the polyamine pathway, which is known to play a key role in cell proliferation.

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

“…Thus, even though Gy\Y cells have no spermine, the accumulation of spermidine was sufficient to affect their ODC activity adversely. This finding is at variance with that of Lorenz et al [26], who found that the ODC activity was elevated in all tissues analysed from Gy\Y mice. The difference is probably due to the fact that the spermidine concentration in the Gy\Y cells by far exceeded those in Gy\Y mouse tissues.…”

“…When the phenotype of Gy mice was compared with that of Hyp mice, many additional defects became apparent. Although the Hyp and Gy mutations both affect the Phex gene, which encodes a neutral endopeptidase with significant homology to members of the membrane-bound metalloendopeptidase family, the Gy deletion extends far beyond the Phex gene and includes the upstream neighbour, the spermine synthase gene [25][26][27]. In fact, the deletion encompasses the entire spermine synthase gene and approx.…”

“…In fact, the deletion encompasses the entire spermine synthase gene and approx. 50 kb upstream of the first exon [26]. The resulting spermine deficiency can probably explain most, if not all, of the additional defects seen in Gy\Y mice.…”

“…The Hyp mouse, which likewise has a deletion in the Phex gene, exhibits a less complex phenotype than does the Gy\Y mouse [23,24]. This appears to be due to the fact that the Gy\Y mouse carries a more extensive deletion, including the neighbouring spermine synthase gene [25][26][27]. The latter is located about 39 kb upstream of the Phex gene.…”

“…This deletion results in barely detectable levels of spermine, and elevated spermidine levels in all tissues examined. The lack of spermine is thought to explain the additional symptoms of the gyro phenotype [26,27]. The Gy\Y mouse represents the first vertebrate model for a major deficiency in the polyamine biosynthetic pathway.…”