Identification of a causative gene responsible for deafness, imbalance, and abnormal EEG in the WTC-dfk rat

• Project/Area Number: 15300141
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Laboratory animal science
• Research Institution: Kyoto University
• Principal Investigator: KURAMOTO Takashi Kyoto University, Graduate School of Medicine, Lecturer, 医学研究科, 講師 (20311409)
• Co-Investigator(Kenkyū-buntansha): KUWAMURA Mitsuru Osaka Prefecture University, Veterinary Pathology, Lecturer, 生命環境科学研究科, 講師 (20244668) ; AKAIKE Akinori Kyoto University, Graduate School of Pharmacology, 薬学研究科, 教授 (80135558)
• Project Period (FY): 2003 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥16,800,000 (Direct Cost: ¥16,800,000); Fiscal Year 2005: ¥4,100,000 (Direct Cost: ¥4,100,000); Fiscal Year 2004: ¥4,100,000 (Direct Cost: ¥4,100,000); Fiscal Year 2003: ¥8,600,000 (Direct Cost: ¥8,600,000)
• Keywords: Potassium channel / Long QT / deafness / achlorhydria / hypertension / disease model / rat / imbalance / ボジショナルクローニング / コアイソジェニック / 低体重 / 行動異常 / ポジショナルクローニング / 突然変異 / 常染色体劣勢遺伝 / 連鎖解析 / 遺伝子マッピング

Research Abstract

KCNQ1 forms K^+ channels by assembly with regulatory subunit KCNE proteins and plays a key role in the K^+ homeostasis in a variety of tissues. In the heart, KCNQ1 is co-assembled with the KCNE1 to produce a cardiac-delayed rectifier K^+ current. In the inner ear, KCNQ1/KNCE1 complex maintains the high concentration of K^+ in the endolymph. In the stomach, KCNQ1 is co-assembled with KCNE2 to form the K^+ exflux channel that is essential for gastric acid secretion. In the colon and small intestine, KCNQ1 is co-assembled with KCNE3 to play an important role in transepithelial cAMP-stimulated Cl^- secretion. For further understanding of Kcnq1 function in vivo, an animal model has been required. Here we reported the identification of a coisogenic Kcnq1 mutant rat, named deafness Kyoto (dfk), and the characterization of its phenotypes. WTC-dfk rats carried intragenic deletion at the Kcnq1 gene, and showed impaired gain of weight, deafness and imbalance resulting from the marked reduction of endolymph, prolonged QT interval in the ECG, and gastric achlorhydria associated with hypertrophic gastric mucosa. Surprisingly, WTC-dfk rats showed hypertension, which suggested that Kcnq1 might be involved in the regulation of blood pressure. These findings suggest that WTC-dfk rats could represent a powerful tool for studying the physiological functions of KCNQ1 and for the establishment of new therapeutic procedures for Kcnq1-related diseases.

Research Products

• [Journal Article] WTC deafness Kyoto (dfk) : a rat model for extensive investigations of Kcnql functions (2006)
  • Author(s): Gohma H, Kuramoto T, et al.
  • Journal Title: Physiological Genomics 24(3) Pages: 198-206
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] WTC deafness Kyoto (dfk) : a rat model for extensive investigations of Kcnq1 functions. (2006)
  • Author(s): Gohma H, Kuramoto T, Kuwamura M, Okajima R, Tanimoto N, Yamasaki K, Nakanishi S, Kitada K, Makiyama T, Akao M, Kita T, Sasa M, Serikawa T
  • Journal Title: Physiol Genomics 24(3) Pages: 198-206
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] WTC deafness Kyoto (dfk) : a rat model for extensive investigation of Kcnq1 functions. (2006)
  • Author(s): Gohma H, Kuramoto T, et al.
  • Journal Title: Physiological Genomics 24(3) Pages: 198-206
• [Journal Article] The rat pink-eyed dilution (p) mutation : An identical intragenic deletion in pink-eye dilute-coat strains and several Wistar-derived albino strains (2005)
  • Author(s): Kuramoto T, Gohma H, et al.
  • Journal Title: Mammalian Genome 16 Pages: 712-719
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Sparse and wavy hair : a new model for hypoplasia of hair follicle and mammary glands on rat chromosome 17. (2005)
  • Author(s): Kuramot T, Morimura K, et al.
  • Journal Title: Journal of Heredity 96(4) Pages: 339-345
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Mutation at the Lmxla locus provokes aberrant brain development in the rat (2005)
  • Author(s): Kuwamura M, et al.
  • Journal Title: Brain Research Developmental Brain Research 155(2) Pages: 99-106
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The rat pink-eyed dilution (p) mutation : An identical intragenic deletion in pink-eye dilute-coat strains and several Wistar-derived albino strains (2005)
  • Author(s): Kuramoto, T., Gohma, H., Kimura, K., Wedkind, D., Hedrich, HJ., Serikawa, T.
  • Journal Title: Mammal Genome 16 Pages: 712-719
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Sparse and wavy hair : a new model for hypoplasia of hair follicle and mammary glands on rat chromosome 17. (2005)
  • Author(s): Kuramoto T, Morimura K, Nomoto T, Namiki C, Hamada S, Fukushima S, Sugimura T, Serikawa T, Ushijima T.
  • Journal Title: J Hered. 96(4) Pages: 339-345
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Mutation at the Lmx1a locus provokes aberrant brain development in the rat. (2005)
  • Author(s): Kuwamura M, Muraguchi T, Matsui T, Ueno M, Takenaka S, Yamate J, Kotani T, Kuramoto T, Guenet JL, Kitada K, Serikawa T.
  • Journal Title: Brain Res Dev Brain Res. 155(2) Pages: 99-106
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The rat pink-eyed dilution (p) mutation : An identical intragenic deletion in pink-eye dilute-coat strains and several Wistar-derived albino strains (2005)
  • Author(s): Kuramoto, T., Gohma, H., et al.
  • Journal Title: Mammalian Genome 16 Pages: 712-719
• [Journal Article] Sparse and wavy hair, a new model for hypoplasia of hair follicles and mammary glands on rat chromosome 17 (2005)
  • Author(s): Kuramoto, T., Morimura, K., et al.
  • Journal Title: Journal of Heredity 96(4) Pages: 339-345
• [Journal Article] Mutation at the Lmxla locus provokes aberrant brain development in the rat (2005)
  • Author(s): Kuwamura, M., et al.
  • Journal Title: Brain Res Dev Brain Res (In press)
• [Journal Article] Immunohistochemical and morphometrical studies on myelin breakdown in the demyelination (dmy) mutant rat (2004)
  • Author(s): Kuwamura M, et al.
  • Journal Title: Brain Research 1022 Pages: 110-116
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The Rat Ruby (R) Locus is Rab38 : Identical Mutations in Fawn-Hooded and Tester-Moriyama Rats Derived from an Ancestral Long Evans Rat Sub-Strain (2004)
  • Author(s): Oiso N, et al.
  • Journal Title: Mammalian Genome 15(4) Pages: 307-314
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Rat neurological mutations cerebellar vermis defect and hobble are caused by mutations in the netrin-1 receptor gene Unc5h3. (2004)
  • Author(s): Kuramoto T, et al.
  • Journal Title: Brain Research Molecular Brain Research 122(2) Pages: 103-108
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] PCR-based genotyping of the rat Atrn^mv mutation (2004)
  • Author(s): Tokuda, et al.
  • Journal Title: Experimental Animals 53(1) Pages: 73-76
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Rat mutations cvd and hob with cerebellar malformations map to Chromosome 2. (2004)
  • Author(s): Kuwamura M, et al.
  • Journal Title: Experimental Animals 53(1) Pages: 21-26
  • NAID: 10011955911
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Immunohistochemical and morphometrical studies on myelin breakdown in the demyelination (dmy) mutant rat. (2004)
  • Author(s): Kuwamura M, Kanehara T, Tokuda S, Kumagai D, Yamate J, Kotani T, Nakane Y, Kuramoto T, Serikawa T.
  • Journal Title: Brain Res. 1022(1-2) Pages: 110-116
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Rat neurological mutations cerebellar vermis defect and hobble are caused by mutations in the netrin-1 receptor gene Unc5h3. (2004)
  • Author(s): Kuramoto, T., Kuwamura, M., Serikawa, T.
  • Journal Title: Brain Res Mol Brain Res. 122(2) Pages: 103-108
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The Rat Ruby (R) Locus is Rab38 : Identical Mutations in Fawn-Hooded and Tester-Moriyama Rats Derived from an Ancestral Long Evans Rat Sub-Strain. (2004)
  • Author(s): Oiso, N., Riddle, SR., Serikawa, T., Kuramoto, T., Spritz, RA.
  • Journal Title: Mamm Genome 15(4) Pages: 307-314
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] PCR-based genotyping of the rat Atrnmv mutation. (2004)
  • Author(s): Tokuda, S., Kuramoto, T., Serikawa, T.
  • Journal Title: Exp Anim 53(1) Pages: 73-76
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Rat mutations cvd and hob with cerebellar malformations map to Chromosome 2. (2004)
  • Author(s): Kuwamura, M., Ando, Y., Takada, A., Kanehara, T., Yamate, J., Kotani, T., Takashita, S., Kanbori, M., Kitada, K., Serikawa, T.
  • Journal Title: Exp Anim 53(1) Pages: 21-26
  • NAID: 10011955911
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Immunohistochemical and morphometrical studies on myelin breakdown in the demvelination (dmv) mutant rat (2004)
  • Author(s): Kuwamura, M., et al.
  • Journal Title: Brain Res 1022 Pages: 110-116
• [Publications] Kuramoto, T., et al.: "Rat neurological mutations cerebellar vermis defect and hobble are caused by mutations in the netrin-1 receptor gene Unc5h3"Brain Res Mol Brain Res. (In press). (2004)
• [Publications] Oiso N., et al.: "The rat Ruby (R) locus is Rab38: identical mutations in Fawn-hooded and Tester-Moriyama rats derived from an ancestral Long Evans rat sub-strain"Mammalian Genome. (In press). (2004)
• [Publications] Tokuda et al.: "PCR-based genotyping of the rat Atrn^<mv> mutation"Experimental Animals. 53(1). 73-76 (2004)
• [Publications] Kuwamura et al.: "Rat mutations cvd and hob with cerebellar malformations map to Chromosome 2"Experimental animals. 53(1). 21-26 (2004)