A natural mouse model reveals genetic determinants of systemic capillary leak syndrome (Clarkson disease)

Abstract

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 we identify an inbred mouse strain, SJL, which recapitulates cardinal features of SCLS, including susceptibility to histamine-and infection-triggered vascular leak. We named this trait "Histamine hypersensitivity" (Histh/Histh) and mapped it to Chromosome 6. Histh is syntenic to the genomic locus most strongly associated with SCLS in humans (3p25.3), revealing that the predisposition to develop vascular hyperpermeability has a strong genetic component conserved between humans and mice and providing a naturally occurring animal model for SCLS. Genetic analysis of Histh may reveal orthologous candidate genes that contribute not only to SCLS, but also to normal and dysregulated mechanisms underlying vascular barrier function more generally.

Genetic Analysis of Bphse: a Novel Gene Complementing Resistance to Bordetella pertussis-Induced Histamine Sensitization

“…Given the evidence from inbred strains of mice indicating that a quarter or more of the mammalian genome consists of chromosomal regions containing clusters of functionally related genes, i.e., functional linkage disequilibrium (LD) domains [32,33], we hypothesized that the dominant locus complementing Hrh1 r /HRH1 r may reside within such a LD domain. Support for the existence of a functional LD domain controlling responsiveness to HA is supported by our recent finding that Histh1-4, four QTL on Chr6:45.9-127.9 Mb controlling age-and inflammationdependent susceptibility to HA-shock in SJL/J, FVB/NJ, NU/J, and SWR/J mice, are in strong LD with Bphs/Hrh1 (Chr6:114,397,483,296 bp) [34,35].…”

“… Pertussis toxin : Bphs is induced in mouse strains by PTX [12]. Vascular permeability (VP): Hypersensitivity to HA exhibits vascular leakage in skin and muscles [34, 35]. Endoplasmic reticulum (ER)/endoplasmic membrane protein complex (EMC), and endoplasmic reticulum-associated degradation (ERAD) : The two HRH1 alleles exhibit differential protein trafficking and cell surface expression with the HRH1 r allele primarily retained in the ER [21].…”

“…The top ten candidates for Bphse as ranked using S cg are: Atg7, Plxnd1, Tmcc1, Mkrn2, Il17re, Pparg, Lhfpl4, Vgll4, Rho and Syn2. It is interesting to note that the predicted candidates for Bphse not only overlap Bphs / Hrh1 but two additional QTLs, Histh3 (Chr6:99.5-112.3 Mb) and Histh4 (Chr6:112.3-127.9 Mb), controlling age- and inflammation-dependent susceptibility to HA shock in SJL/J, FVB/NJ, NU/J, and SWR/J mice [34, 35]. Importantly, our findings support the existence of a smaller functional LD domain on Chr6:111.0-116.4 Mb (∼5.5 Mb interval) that controls susceptibility to HA-shock elicited by both PTX dependent and independent mechanisms (Supplementary Figure 2).…”

“…Importantly, the fact that Bphse resides within a smaller functional LD that includes Histh3 and Histh4 (Supplementary Figure 2) is of potential clinical significance. Histh is an autosomal recessive genetic locus that controls susceptibility to B. pertussis and PTX-independent, age- and inflammation-dependent HA-shock in SJL/J mice [34, 35]. Four sub-QTLs ( Histh1-4 ) define Histh , each contributing 17%, 19%, 14%, and 10%, respectively, to the overall penetrance of Histh.…”

“…SCLS or Clarkson disease is a rare disease 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. Additionally, Histh s SJL/J mice recapitulate many of the cardinal features of SCLS, including susceptibility to HA- and infection-triggered vascular leak and the clinical diagnostic triad of hypotension, elevated hematocrit, and hypoalbuminemia and as such makes them a natural occurring animal model for SCLS [34, 35]. Clearly, detailed genetic analysis and identification of the causative genes underlying Bphse , Histh3 , and Histh4 may reveal orthologous candidate genes and or pathways that contribute not only to SCLS, but also to normal and dysregulated mechanisms underling vascular barrier function more generally.…”