Nigsq1^C57BL/6J
QTL Variant Detail

Summary

• QTL variant: Nigsq1^C57BL/6J
• Name: neuroglucopenia-induced glucagon secretion QTL 1; C57BL/6J
• MGI ID: MGI:5904598
• QTL: Nigsq1 Location: unknown Genetic Position: Chr7, Syntenic

Variant origin

• Strain of Specimen: C57BL/6J

Variant description

• Allele Type: QTL

Notes

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

J:240974

The counterregulatory response to hypoglycemia, which restores normal blood glucose levels to ensure sufficient provision of glucose to the brain, is critical for survival. To discover underlying brain regulatory systems, a genetic screen in recombinant inbred mice for quantitative trait loci (QTL) controlling glucagon secretion in response to neuroglucopenia was performed in the current study.

A panel of 36 BXD recombinant mouse strains, which were derived from crossing C57BL/6J x DBA/2J mice, were were searcher for genomic intervals associated with glucagon secretion induced by by 2DG-induced neuroglucopenia.

Ten week old, male mice from each strain were injected with a saline solution and blood was collected 30 minutes later for plasma preparation and storage. Two weeks later the mice received an injection of 2DG and blood was collected and prepared. Glucagon levels were measured by radioimmunoassay for all mice and the ratio between plasma glucagon after 2DG and NaCl injections was calculated.

The trait varied by 3-fold between BXD stains with the lowest response, 1.5-fold, detected in BXD49 and the highest, 4.7-fold, in BXD50. [Fig 1A.] QTL analysis detected a whole genome significant (p<0.05) QTL on the distal part of Chromosome 7. The QTL Nigsq1, neuroglucopenia-induced glucagon secretion QTL 1, mapped to Chr 7 peaking at marker rs234086585 between flanking markers c7.loc119 (147.5303 MB) and rs31652431 (152.411 Mb). The locus was ~5 Mb wide, contained 128 genes and accounted for 49% of varianace in the glucagon trait.

MGI Curator Note: SNP rs234086585 is a correction of the SNP reported within the text [rs2304086585].

To narrow down the genes within the QTL, which could regulate glucagon secretion, it was hypothesized, that the genes these must be expressed in the hypothalamus where glucose sensitive neurons are located and that their level of expression must correlate with the glucagon phenotype, assuming that they are non-coding polymorphisms. Transcriptomic analysis of the hypothalamus was performed from all the BXD strains using mice that had not undergone QTL screening.

The hypothalamic expression level of 11 genes was significantly correlated to the glucagon trait. Fgf15 mRNA was the most significantly, and negatively, correlated to the glucagon phenotype. The second gene in this table, which shows a similar high correlation with the trait as Fgf15 is Gm17685 . [Table 1]. Gm17685 encodes a long non-coding RNA transcribed in reverse orientation from exon 2 of Fgf15, and its expression is highly correlated with that of Fgf15. Furthermore, the Fgf15 gene of the DBA/2J and C57BL/6 mice encodes the same amino acid sequence, supporting differential expression of this gene as a possible underlying cause of the glucagon trait.

References

• Original: J:240974 Picard A, et al., A Genetic Screen Identifies Hypothalamic Fgf15 as a Regulator of Glucagon Secretion. Cell Rep. 2016 Nov 08;17(7):1795-1806
• All: 1 reference(s)