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MOLECULAR GENETICS OF HUMAN LEFT-RIGHT AXIS MALFORMATIONS

Research Project

Project/Area Number 11670785
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionKEIO UNIVERSITY

Principal Investigator

KOSAKI Kenjiro  KEIO UNIVERSITY, SCHOOL OF MEDICINE, ASSISTANT PROFESSOR, 医学部, 専任講師 (30234743)

Co-Investigator(Kenkyū-buntansha) KOSAKI Rika  KEIO UNIVERSITY, HEALTH CENTER ASSISTANT, 付属研究所, 助手 (50234745)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2000: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1999: ¥2,200,000 (Direct Cost: ¥2,200,000)
KeywordsSITUS INVERSUS / SITUS AMBIGUUS / LEFT-RIGHT AXIS / MUTATION ANALYSIS / CONGENITAL MALFORMATIONS / 先天性心疾患 / 遺伝子変異
Research Abstract

1) In the inv/inv mouse strain, integration of the tyrosinase minigene causes complete mirror image reversal of internal organs. Analysis of the transgenic integration site revealed that loss of function mutation of a novel gene, Inversin, is responsible for the disruption of normal left-right polarity. Based on these results, we hypothesized that mutations in the Inversin gene are associated with some cases of left-right axis malformations in humans. We cloned of the human INVERSIN cDNA, characterized its genomic structure, and screened for mutations among 112 sporadic and 14 familial cases of left-right axis malformations. We demonstrated that human INVERSIN, localizes to chromosome 9q3l, and encodes a protein with 9O% homology to the mouse homologue. Mutation analysis revealed 2 unique nucleotide substitutions, S371G and A650P which result in missense mutations. We conclude from the current study that INVERSIN mutations are rarely associated with human left-right axis malformations.
2) Bioinformatic analyses of the human/mouse genome sequences of the flanking the lefty gene region revealed that mouse Lefty 1 is the ortholog of human LEFTY2 (also known as LEFTYB). Right sided silencer element of the mouse Lefty 1 is conserved in humans as well. Mutation analysis of more than one hundred patients with situs abnormalities, however, did not reveal any patients with LEFTY2 coding mutations.
3) Left-right axis malformations is commonly observed in the F1 offspring of NOD (non-obese diabetic) mouse dams and sires from ICR strains. The ICR strain had 1) a 0.2 kb insertion in the putative promoter region of the isoform E of Hnf3beta together with a G to A change that could create a potential splice acceptor in the exon 3 of Hnf3beta (gene frequency 0.36), 2) five single base substitutions within the 5' controlling element and a proline to serine substitution (P2S) of Lefty1 (0.77). These substitutions may contribute to increased susceptibility to maternal diabetes.

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (10 results)

All Other

All Publications (10 results)

  • [Publications] Katsuhiro Maeyama et al: "Muation analysis of left-right axis determining genes in NOD and FCR strains susceptible to maternal diabetes"Teratology. (印刷中). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 小崎健次郎: "左右軸を決定する遺伝子"小児科診療. 63.(12). 126-127 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 小崎健次郎 他: "糖尿病母体児の奇形の実態と研究の展望"Diabetes Frontier. 10(5). 690-695 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kenjiro Kosaki et al: "Characterization and mutation analysis of human LEFTYA and LEFTYB homologues of murine genes implicated in left-right axis devebpment"American Journal of Human Genetics. 64. 712-721 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kosaki K, Bassi MT, Kosaki R, Lewin M, Belmont J, Schauer G, Casey B: "Characterization and mutation analysis of human LEFTY A and LEFTY B, homologues of murine genes implicated in left-right axis development."American Journal of Human Genetics. 64. 712-721 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Maeyama K, Kosaki R, Yoshihashi H, Casey B, Kosaki K.: "Mutation analysis of left-right axis determining genes in NOD and ICR, strains susceptible to maternal diabetes."Teratology. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Katsuhiro Maeyama: "Mutation analysis of left-right axis determining genes in NOD and ICR, strairs susceptible to maternal diabetes"Teratology. (印刷中). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] 小崎健次郎: "左右軸を決定する遺伝子"小児科診療. 63(12). 126-127 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kenjiro Kosaki: "Characterization and mutation analysis of human LEFTYA and LEFTY B"American Journal of Human Genetics. 64(3). 712-721 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Rika Kosaki: "Mutation analysis of human Hnf3 beta, Smad2 and Nodal in NOD mouse"American Journal of Human Genetics. 65(4). A2607 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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