Sweating is an essential process that regulates body temperature in response to a variety of thermal stress. Individuals unable to sweat cannot tolerate heat and are at increased risk for developing heat-related illnesses, possibly leading to death. The inability to sweat (anhidrosis) has multiple causes, including injury and certain medications; however, there is likely a genetic component in some cases. Joakim Klar, Chihiro Hisatsune, and colleagues at Uppsala University and Riken University evaluated a family in which several members presented with anhidrosis. Whole genome sequencing revealed that the affected family members were homozygous for a missense mutation in ITPR2, which encodes the ER-localized Ca2+ release channel InsP3R2. Intracellular Ca2+ release in sweat gland clear cells induces sweat production, and Ca2+ release was inhibited in cells expressing mutant InsP3R2. Moreover, mice lacking InsP3R2 had reduced sweat secretion, and evaluation of sweat glands from these animals revealed a defect in Ca2+ release. The results from this study demonstrate that loss of InsP3R2 function is a source of anhidrosis and suggest that limiting InsP3R2 activity has potential to reduce sweat production in hyperhidrosis. The accompanying video shows the generation of Ca2+ signals in sweat glands isolated from WT mice following stimulation with acetylcholine.
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
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