Spermine synthase deficiency leads to deafness and a profound sensitivity to α-difluoromethylornithine

Xiaojing Wang, Snezana Levic, Michael Anne Gratton, Karen Jo Doyle, Ebenezer N. Yamoah, Anthony Pegg

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Male gyro (Gy) mice, which have an X chromosomal deletion inactivating the SpmS and Phex genes, were found to be profoundly hearing impaired. This defect was due to alteration in polyamine content due to the absence of spermine synthase, the product of the SpmS gene. It was reversed by breeding the Gy strain with CAG/SpmS mice, a transgenic line that ubiquitously expresses spermine synthase under the control of a composite cytomegalovirus-IE enhancer/chicken β-actin promoter. There was an almost complete loss of the endocochlear potential in the Gy mice, which parallels the hearing deficiency, and this was also reversed by the production of spermine from the spermine synthase transgene. Gy mice showed a striking toxic response to treatment with the ornithine decarboxylase inhibitor α-diflu-oromethylornithine (DFMO). Within 2-3 days of exposure to DFMO in the drinking water, the Gy mice suffered a catastrophic loss of motor function resulting in death within 5 days. This effect was due to an inability to maintain normal balance and was also prevented by the transgenic expression of spermine synthase. DFMO treatment of control mice or Gy-CAG/SpmS had no effect on balance. The loss of balance in Gy mice treated with DFMO was due to inhibition of polyamine synthesis because it was prevented by administration of putrescine. Our results are consistent with a critical role for polyamines in regulation of Kir channels that maintain the endocochlear potential and emphasize the importance of normal spermidine:spermine ratio in the hearing and balance functions of the inner ear.

Original languageEnglish (US)
Pages (from-to)930-937
Number of pages8
JournalJournal of Biological Chemistry
Volume284
Issue number2
DOIs
StatePublished - Jan 9 2009

Fingerprint

Spermine Synthase
Eflornithine
Deafness
Polyamines
Audition
Spermine
Hearing
Genes
Putrescine
Spermidine
Poisons
Drinking Water
Actins
Inner Ear
Cytomegalovirus
Transgenes
Defects
Transgenic Mice
Breeding
Chickens

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Wang, Xiaojing ; Levic, Snezana ; Gratton, Michael Anne ; Doyle, Karen Jo ; Yamoah, Ebenezer N. ; Pegg, Anthony. / Spermine synthase deficiency leads to deafness and a profound sensitivity to α-difluoromethylornithine. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 2. pp. 930-937.
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abstract = "Male gyro (Gy) mice, which have an X chromosomal deletion inactivating the SpmS and Phex genes, were found to be profoundly hearing impaired. This defect was due to alteration in polyamine content due to the absence of spermine synthase, the product of the SpmS gene. It was reversed by breeding the Gy strain with CAG/SpmS mice, a transgenic line that ubiquitously expresses spermine synthase under the control of a composite cytomegalovirus-IE enhancer/chicken β-actin promoter. There was an almost complete loss of the endocochlear potential in the Gy mice, which parallels the hearing deficiency, and this was also reversed by the production of spermine from the spermine synthase transgene. Gy mice showed a striking toxic response to treatment with the ornithine decarboxylase inhibitor α-diflu-oromethylornithine (DFMO). Within 2-3 days of exposure to DFMO in the drinking water, the Gy mice suffered a catastrophic loss of motor function resulting in death within 5 days. This effect was due to an inability to maintain normal balance and was also prevented by the transgenic expression of spermine synthase. DFMO treatment of control mice or Gy-CAG/SpmS had no effect on balance. The loss of balance in Gy mice treated with DFMO was due to inhibition of polyamine synthesis because it was prevented by administration of putrescine. Our results are consistent with a critical role for polyamines in regulation of Kir channels that maintain the endocochlear potential and emphasize the importance of normal spermidine:spermine ratio in the hearing and balance functions of the inner ear.",
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Spermine synthase deficiency leads to deafness and a profound sensitivity to α-difluoromethylornithine. / Wang, Xiaojing; Levic, Snezana; Gratton, Michael Anne; Doyle, Karen Jo; Yamoah, Ebenezer N.; Pegg, Anthony.

In: Journal of Biological Chemistry, Vol. 284, No. 2, 09.01.2009, p. 930-937.

Research output: Contribution to journalArticle

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