Mutation analysis of left-right axis determining genes in NOD and ICR, strains susceptible to maternal diabetes

Katsuhiro Maeyama, Rika Kosaki, Hiroshi Yoshihashi, Brett Casey, Kenjiro Kosaki

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background: Genetic background of the fetus contributes to the pathogenesis of congenital malformation after teratogen exposure. Such contribution is illustrated in left-right axis malformations observed in the F1 offspring of nonobese diabetic (NOD) mouse dams and sires from different strains. When sires of the NOD, ICR, or C57BL/6J were mated with NOD dams, incidence varied depending on the fetal genotype, with 65% in NOD × NOD, 24% in NOD × ICR, and 7% in NOD × C57BL/6J. Methods: As a first step in elucidating the molecular basis of the interstrain differences in susceptibility to situs defects, we compared genomic sequences of six genes HNF3beta, Acvr2b, Nodal, ZIC3, Lefty1, and Smad2, which are involved in the normal development of left-right axis among NOD, ICR, and C57BL/6J strains. Results: The outbred strain ICR 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 P = 0.36), 2) five single base substitutions within the 5′ controlling element and a proline to serine substitution (P2S) of Lefty1 (P = 0.77), and 3) a tyrosine to histidine substitution within the prodomain of Nodal (P = 0.48). The inbred strain NOD had the same G to A change as ICR and a three-base deletion in the putative promoter of isoform E of HNF3β. Conclusions: We suggest that sequence variations in HNF3β, Lefty1, and Nodal might account, in part, for the interstrain differences in susceptibility to situs abnormalities among the offspring of diabetic dams.

Original languageEnglish
Pages (from-to)119-126
Number of pages8
JournalTeratology
Volume63
Issue number3
DOIs
Publication statusPublished - 2001 Apr 10

ASJC Scopus subject areas

  • Embryology
  • Toxicology
  • Developmental Biology
  • Health, Toxicology and Mutagenesis

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