Abolished InsP₃R2 function inhibits sweat secretion in both humans and mice

• Text
• PDF

Abstract

There are 3 major sweat-producing glands present in skin; eccrine, apocrine, and apoeccrine glands. Due to the high rate of secretion, eccrine sweating is a vital regulator of body temperature in response to thermal stress in humans; therefore, an inability to sweat (anhidrosis) results in heat intolerance that may cause impaired consciousness and death. Here, we have reported 5 members of a consanguineous family with generalized, isolated anhidrosis, but morphologically normal eccrine sweat glands. Whole-genome analysis identified the presence of a homozygous missense mutation in ITPR2, which encodes the type 2 inositol 1,4,5-trisphosphate receptor (InsP₃R2), that was present in all affected family members. We determined that the mutation is localized within the pore forming region of InsP₃R2 and abrogates Ca²⁺ release from the endoplasmic reticulum, which suggests that intracellular Ca²⁺ release by InsP₃R2 in clear cells of the sweat glands is important for eccrine sweat production. Itpr2^–/– mice exhibited a marked reduction in sweat secretion, and evaluation of sweat glands from Itpr2^–/– animals revealed a decrease in Ca²⁺ response compared with controls. Together, our data indicate that loss of InsP₃R2-mediated Ca²⁺ release causes isolated anhidrosis in humans and suggest that specific InsP₃R inhibitors have the potential to reduce sweat production in hyperhidrosis.

Authors

Joakim Klar, Chihiro Hisatsune, Shahid M. Baig, Muhammad Tariq, Anna C.V. Johansson, Mahmood Rasool, Naveed Altaf Malik, Adam Ameur, Kotomi Sugiura, Lars Feuk, Katsuhiko Mikoshiba, Niklas Dahl