title: Abolished InsP3R2 function inhibits sweat secretion in both humans and mice.
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.forename: Joakim
authors.initials: J
authors.lastname: Klar
authors.forename: Chihiro
authors.initials: C
authors.lastname: Hisatsune
authors.forename: Shahid M
authors.initials: SM
authors.lastname: Baig
authors.forename: Muhammad
authors.initials: M
authors.lastname: Tariq
authors.forename: Anna C V
authors.initials: AC
authors.lastname: Johansson
authors.forename: Mahmood
authors.initials: M
authors.lastname: Rasool
authors.forename: Naveed Altaf
authors.initials: NA
authors.lastname: Malik
authors.forename: Adam
authors.initials: A
authors.lastname: Ameur
authors.forename: Kotomi
authors.initials: K
authors.lastname: Sugiura
authors.forename: Lars
authors.initials: L
authors.lastname: Feuk
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mikoshiba
authors.forename: Niklas
authors.initials: N
authors.lastname: Dahl
mesh_terms: D000109:Acetylcholine / Q000502:physiology; D000818:Animals; D001833:Body Temperature Regulation; D020013:Calcium Signaling; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D006801:Humans; D007007:Hypohidrosis / Q000235:genetics*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics*; D008126:Lod Score; D008297:Male; D018345:Mice, Knockout; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D013546:Sweating / Q000235:genetics*
chemical_list: C506927:ITPR2 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D000109:Acetylcholine