Hyperchlorhidrosis caused by homozygous mutation in CA12, encoding carbonic anhydrase XII |
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Authors: | Feldshtein Maya Elkrinawi Suliman Yerushalmi Baruch Marcus Barak Vullo Daniela Romi Hila Ofir Rivka Landau Daniel Sivan Sara Supuran Claudiu T Birk Ohad S |
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Institution: | 1 Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev (NIBN), Ben Gurion University, Beer-Sheva, 84105 Israel 2 Division of Pediatrics, Soroka University Medical Center, Beer-Sheva, 84101 Israel 3 Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy 4 Genetics Institute, Soroka University Medical Center, Beer-Sheva, 84101 Israel |
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Abstract: | Excessive chloride secretion in sweat (hyperchlorhidrosis), leading to a positive sweat test, is most commonly indicative of cystic fibrosis yet is found also in conjunction with various metabolic, endocrine, and dermatological disorders. There is conflicting evidence regarding the existence of autosomal-recessive hyperchlorhidrosis. We now describe a consanguineous Israeli Bedouin kindred with autosomal-recessive hyperchlohidrosis whose sole symptoms are visible salt precipitates after sweating, a preponderance to hyponatremic dehydration, and poor feeding and slow weight gain at infancy. Through genome-wide linkage analysis, we demonstrate that the phenotype is due to a homozygous mutation in CA12, encoding carbonic anhydrase XII. The mutant (c.427G>A p.Glu143Lys]) protein showed 71% activity of the wild-type enzyme for catalyzing the CO2 hydration to bicarbonate and H+, and it bound the clinically used sulfonamide inhibitor acetazolamide with high affinity (KI of 10 nM). Unlike the wild-type enzyme, which is not inhibited by chloride, bromide, or iodide (KIs of 73–215 mM), the mutant is inhibited in the submicromolar range by these anions (KIs of 0.37–0.73 mM). |
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