Hipq1^DBA/2Wehi
QTL Variant Detail

Summary

• QTL variant: Hipq1^DBA/2Wehi
• Name: hyperinsulin production QTL 1; DBA/2Wehi
• MGI ID: MGI:3770307
• QTL: Hipq1 Location: Chr13:110409487-119476372 bp Genetic Position: Chr13, Syntenic

Variant origin

• Strain of Specimen: DBA/2Wehi

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers increased insulin secretion compared to C57BL/6Wehi. (J:129498)

Expression

In Structures Affected by this Mutation:

1 anatomical structure(s)

Notes

Mapping and Phenotype information for this QTL, its variants and associated markers

J:129498

A population of 171 male (C57BL/6Wehi x DBA/2Wehi)F2 x C57BL/6Wehi backcross animals were used to identify QTLs associated with insulin hypersecretion. Experimental animals were phenotyped by intravenous glucose tolerance test (IVTT). Parental strain DBA/2J exhibits high insulin secretion and diabetes susceptibility compared to C57BL/6Wehi. Insulin hypersecretion was observed in 23% of backcross mice and these animals were used for genome scan.

Significant linkage to hyperinsulin secretion mapped to mouse Chromosome 13 between D13Mit130 (61 cM) and D13Mit35 (75 cM) with LOD=7.7. This locus is named Hipq1 (hyperinsulin production QTL 1). DBA/2Wehi-derived alleles at Hipq1 confers insulin increased secretion. Recombinant inbred strain analysis using BXD-28 and BXD-12 lines further narrowed the Hipq1 interval to a 2 Mb region near the chromosome 13 telomere. Expression analysis was performed on seven genes found in this interval. Nnt (64 cM) displayed over 5-fold increased expression in DBA/2Wehi mice compared to C57BL/6Wehi mice. Sequence analysis of Nnt revealed a 5 exon deletion in the C57BL/6Wehi gene sequence. This deletion is not present in DBA/2Wehi, FVB/N, BALB/c, or 129T2 strains. A previously identified glucose tolerance QTL named Gluchos1 (73cM) overlaps with Hipq1. Nnt was also named a potential candidate gene forGluchos1.

A congenic line carrying a DBA/2Wehi-derived Hipq1 locus with Fgf10 (75 cM) and Nnt genetic sequences on a C57BL/6Wehi background was constructed. Nnt expression increased2.5-fold and Nnt activity increased3-fold in congenic animals. However, challenge with IVTT and intraperitoneal glucose tolerance test (IPGTT) showed congenic animals did not have abnormal insulin secretion or glucose tolerance. The reciprocal congenic line carrying a C57BL/6Wehi-derived Hipq1 locus on a DBA/2Wehi genetic background had the expected opposite effect of decreasing Nnt expression and activity. Challenge with IVTT and IPGTT showed reduced first-phase insulin levels and decreased glucose tolerance in the reciprocal congenic. It appears Hipq1 is necessary but not sufficient for the insulin hypersecretion and glucose tolerance phenotype seen in DBA/2Wehi parental animals. Authors hypothesize a second yet identified QTL may influence Nnt expression, insulin secretion, and diabetes susceptibility.

References

• Original: J:129498 Aston-Mourney K, et al., Increased nicotinamide nucleotide transhydrogenase levels predispose to insulin hypersecretion in a mouse strain susceptible to diabetes. Diabetologia. 2007 Dec;50(12):2476-85
• All: 1 reference(s)