Sequence analysis of Tnf as a candidate for Idd16.
Linkage analysis and congenic mapping have localized 18 loci (Idd1-18) that contribute to the development of autoimmune type 1 diabetes in the nonobese diabetic (NOD) mouse. By using a congenic NOD strain which possesses recombinant MHC from a closely related CTS strain, a susceptible region (Idd16) was mapped to the segment adjacent to, but distinct from class II A and E genes (Idd1). The tumor necrosis factor alpha gene (Tnf), which is located within the Idd16 region, has been suspected to be a candidate gene for type 1 diabetes in the NOD mouse. Although the protein-coding region in Tnf has been sequenced in the NOD mouse and its related strains, the complete upstream region (approximately 1400 bp, including the 5'-untranslated region) has not yet been studied. To study the possible contribution of the transcriptional regulation of Tnf to susceptibility to type 1 diabetes, we determined the complete nucleotide sequences of the NOD strain and its related strain, CTS, in comparison with the non-diabetic control strain, C57BL/6. The nucleotide sequence of the 5'-upstream region in the NOD mouse was identical to that in the C57BL/6 mouse, but different from that in the CTS mouse. In particular, a C to A substitution at position 3408 in the CTS mouse creates a new GATA family binding site, which may be responsible for the lower incidence of type 1 diabetes in the NOD. CTS-H-2 congenic strain despite the presence of the same class II MHC.
Babaya
Naru
N
Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
Ikegami
Hiroshi
H
Fujisawa
Tomomi
T
Ueda
Hironori
H
Nojima
Koji
K
Itoi-Babaya
Michiko
M
Yamada
Kazunori
K
Kawaguchi
Yoshiko
Y
Yamato
Eiji
E
Makino
Susumu
S
Ogihara
Toshio
T
D020121:5' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D004247:DNA / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D005802:Genes, MHC Class II; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D012689:Sequence Homology, Nucleic Acid; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D020121:5' Untranslated Regions; D014409:Tumor Necrosis Factor-alpha; D004247:DNA