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

18 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

Fingerprint

Medical problems
Dams
Protein Isoforms
Substitution reactions
Genes
Mothers
Teratogens
Inbred NOD Mouse
Mutation
Histidine
Genetic Promoter Regions
Proline
Gene Frequency
Serine
Exons
Fetus
Genotype
Tyrosine
Incidence
Defects

ASJC Scopus subject areas

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

Cite this

Mutation analysis of left-right axis determining genes in NOD and ICR, strains susceptible to maternal diabetes. / Maeyama, Katsuhiro; Kosaki, Rika; Yoshihashi, Hiroshi; Casey, Brett; Kosaki, Kenjiro.

In: Teratology, Vol. 63, No. 3, 2001, p. 119-126.

Research output: Contribution to journalArticle

Maeyama, Katsuhiro ; Kosaki, Rika ; Yoshihashi, Hiroshi ; Casey, Brett ; Kosaki, Kenjiro. / Mutation analysis of left-right axis determining genes in NOD and ICR, strains susceptible to maternal diabetes. In: Teratology. 2001 ; Vol. 63, No. 3. pp. 119-126.
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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.",
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