Mapping Data

Experiment

• Experiment
  TEXT-QTL-Candidate Genes
• Chromosome
  16
• Reference
  J:287566 Plante JA, et al., Mucin 4 Protects Female Mice from Coronavirus Pathogenesis. bioRxiv. 2020;
• ID
  MGI:6423110

Genes

Gene	Assay Type
Muc4	visible phenotype

Notes

• Experiment
  Using incipient lines of the Collaborative Cross (CC), a murine genetic reference population, the authors previously identified a QTL associated with low SARS-CoV titer (Hrsq2). The initial screen within an incompletely inbred set of CC mice (the preCC screen) (Gralinski et al., 2015), along with an F2 screen utilizing a highly resistant and highly susceptible CC mouse line (Gralinski et al., 2017), identified nine QTL impacting SARS-CoV disease. Among these QTL was locus Hrsq2 on chromosome 16, which was identified as modulating SARS-CoV titer levels in the lung (Gralinski et al., 2015).
  
  * Curator Note: Hrsq2 (MGI:6403752) was originally identified in Gralinski et al., 2015 as HrS2. Due to nomenclature policy within MGI, the locus was renamed Hrsq2. *
  
  In the present study, the authors narrow the Hrsq2 locus to a priority candidate gene, mucin 4 (Muc4), via the integration of sequence data from the CC founders (Keane et al., 2011) and RNA expression results from our preCC experiment. Low expression of Muc4 in mice containing the PWK/PhJ allele corresponded with the low SARS-CoV titer associated with the QTL located at locus Hrsq2.
  
  To test the hypothesis that Muc4 controls SARS-CoV titer in the lung, the authors infected B6NTac.129(FVB)-Muc4^tm1Unc/Rand mice and found that female, but not male, mice with the Muc4^tm1Unc allele developed more weight loss and disease following infection with SARS-CoV. Female mice with the Muc4^tm1Unc allele also had more difficulty breathing despite reduced lung pathology; however, no change in viral titers was observed. Comparing across viral families, studies with chikungunya virus, a mosquito-borne arthralgic virus, suggests that Muc4s impact on viral pathogenesis may be widespread. Although not confirming the original titer QTL, the data identify a role for Muc4 in the SARS-CoV disease and viral pathogenesis.
  
  This work suggests that Muc4 expression plays a protective role in female mice not conserved in male mice following SARS-CoV infection. Treatments that modulate or enhance Muc4 activity may provide an avenue for treatment and improved outcomes. In addition, the work highlights the importance of studying host factors including host genetics and biological sex as key parameters influencing infection and disease outcomes. It is important to note that in this study, the Muc4^tm1Unc allele was introduced on a C57BL/6J background, and the Muc4^PWK/PhJ allele (MGI:6423091) was not directly studied.