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Abolished InsP3R2 function inhibits sweat secretion in both humans and mice
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0003-4185-7409
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2014 (English)In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 124, no 11, 4773-4780 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2014. Vol. 124, no 11, 4773-4780 p.
National Category
Other Clinical Medicine
URN: urn:nbn:se:uu:diva-238427DOI: 10.1172/JCI70720ISI: 000344203300014PubMedID: 25329695OAI: oai:DiVA.org:uu-238427DiVA: diva2:772120
Swedish Research Council, K2013-66X-10829-20-3, 621-2009-4629

De två första författarna delar förstaförfattarskapet.

Available from: 2014-12-16 Created: 2014-12-12 Last updated: 2016-02-29Bibliographically approved

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Klar, JoakimAmeur, AdamFeuk, LarsDahl, Niklas
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Medical GeneticsScience for Life Laboratory, SciLifeLabDepartment of Immunology, Genetics and PathologyGenomics
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