Genomic Association of Chronic Idiopathic Anhidrosis to a Potassium Channel Subunit in a Large Animal Model

Abstract

Similar to humans, the horse relies predominantly on the evaporation of sweat from the skin surface to dissipate excess body heat. Loss of the sweat response or anhidrosis can result in life-threatening hyperthermia. Anhidrosis occurs more frequently in some breeds as well as occurs at an increased frequency among individuals with a family history, suggesting a heritable component to the pathology. Given the natural occurrence and indications of genetic components in the etiology, we utilized genomics to better understand the molecular mechanisms involved in sweat response. We performed a case-control (n ¼ 200) GWAS targeting cases of chronic idiopathic anhidrosis in a controlled genetic background to discover the contributing regions and interrogated gene function for roles in the sweating mechanism. A region containing the KCNE4 gene, which encodes the b-subunit of a potassium channel protein with a possible function in sweat gland outflow, was associated (P ¼ 1.13 Â 10 -07 ) with chronic idiopathic anhidrosis through GWAS. A candidate mutation (NC_009149.3:g.11813731A > G, rs68643109) disrupting the KCNE4 protein structure could explain the disease but requires further investigation in larger populations. We show the potential role of ion channels and cellular damage in sweat response, correlating anhidrosis as a possible effect of congenital channelopathy.

Ion Channel and Ubiquitin Differential Expression during Erythromycin-Induced Anhidrosis in Foals

“…Calcium is also an essential intracellular messenger for purinoreceptor-mediated sweat in horses [ 82 ]. The impaired calcium influx could lead to accumulation of K + ions within the sweat-gland lumen, increasing extracellular/sweat K + respective concentration in anhidrotic individuals [ 83 ]. A similar increase in relative sweat K + concentration is observed in sweat from chronic anhidrotic adult horses [ 66 , 83 ].…”

“…Sweating in horses is dependent upon the actions of circulating epinephrine [ 91 , 92 ] and equine sweat glands are primarily under β-adrenergic control [ 93 ]. The involvement of β-adrenoreceptor pathways could be one trigger for equine idiopathic anhidrosis [ 16 , 83 , 91 , 92 ]. Appropriate downregulation of β 2 -AR is crucial for normal function of diverse biological processes, as it acts in an anti-regulatory mechanism through ubiquination [ 94 ].…”