Mapping Data

Experiment

• Experiment
  TEXT-QTL
• Chromosome
  6
• Reference
  J:281151 Raza A, et al., A natural mouse model reveals genetic determinants of systemic capillary leak syndrome (Clarkson disease). Commun Biol. 2019;2:398
• ID
  MGI:6400460

Genes

Gene	Assay Type
Histh5	visible phenotype
Histh6	visible phenotype

Notes

• Experiment
  The systemic capillary leak syndrome (SCLS, Clarkson disease) is a disorder of unknown etiology characterized by recurrent episodes of vascular leakage of proteins and fluids into peripheral tissues, resulting in whole-body edema and hypotensive shock. The pathologic mechanisms and genetic basis for SCLS remain elusive. Here, the authors identify an inbred mouse strain, SJL/J, which recapitulates cardinal features of SCLS, including susceptibility to histamine- and infection-triggered vascular leak. The authors named this trait Histamine hypersensitivity (Hhs/Hhs) and mapped it to Chromosome 6.
  
  To map the gene or genes controlling Hhs, the authors treated ~478 (B10.S-H2^s/SgMcdJ x SJL/J) F2 mice with histamine at 30 days after priming with CFA and performed genetic association analysis using pre-established genomic markers (Rhodes, M. et al. A high-resolution microsatellite map of the mouse genome. Genome Res. 8, 531542 (1998)).
  
  A genome scan using microsatellite markers that distinguish Hhs-resistant B10.S-H2^s/SgMcdJ and Hhs-susceptible SJL/J mice identified a QTL on Chr 6 within an approximately ~100 Mb region between D6Mit74 (48.72 Mb) to D6Mit372 (148.45 Mb) (p = 5.73 x 10^-5). In addition, there were minor linkages to Chr 8 (p = 2.80 x 10^-2) and Chr 15 (p = 9.74 x 10^-4). The authors designated the locus on Chr 6 as Hhs (histamine hypersensitivity), but the nomenclature was changed to reflect MGD policy:
  
  Histh5 (histamine hypersensitivity 5) maps to Chr 6: 48.72 - 148.45 Mb (D6Mit74 - D6Mit372) with a p-value of 5.73 x 10^-5.
  
  The authors then confirmed the existence and location of Histh5 on Chr 6 by congenic mapping. They used marker-assisted selection to introgress the Histh5 interval (D6Mit74 (48.72 Mb) through D6Mit254 (125.36 Mb) from SJL/J onto the B10.S/SgMcdJ background. These mice were backcrossed for 12 generations and fixed as a homozygous interval-specific recombinant congenic line (ISRCL) hereafter referred to as B10.S-H2^s/SgMcdJ-Histh5^SJL/J (B10.S-Hhs^SJL in the manuscript). The Histh5 phenotype was confirmed by testing susceptibility to histamine challenge 30 days after priming with CFA as above. Lethality due to Histh5 differed significantly among the strains (X^2 = 51.61, df = 1, p < 0.0001); SJL/J and B10.S-H2^s/SgMcdJ-Histh5^SJL/J mice were significantly more susceptible to CFA/histamine than were B10.S-H2^s/SgMcdJ mice (X^2 = 55.24, df = 1, p < 0.0001 for both strains), but their responses did not differ significantly from each other. Moreover, (B10.S-H2^s/SgMcdJ x B10.S-H2^s/SgMcdJ-Histh5^SJL/J) F1 hybrids were Hhs-resistant, confirming the observation made earlier regarding histamine hypersensitivity as a recessive trait. Thus, the authors physically mapped hypersensitivity to Chr 6: 48 - 125 Mb and demonstrated that this locus is sufficient to provide full penetrance of the histamine hypersensitivity phenotype.
  
  This narrowed QTL interval has been named Histh6 (histamine hypersensitivity 6) in accordance with MGD curatorial policy, and maps to Chr 6: 48.72 - 125.36 Mb (D6Mit74 - D6Mit254).