Hyperchlorhidrosis caused by homozygous mutation in CA12, encoding carbonic anhydrase XII

Maya Feldshtein, Suliman Elkrinawi, Baruch Yerushalmi, Barak Marcus, Daniela Vullo, Hila Romi, Rivka Ofir, Daniel Landau, Sara Sivan, Claudiu T. Supuran, Ohad S. Birk

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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).

Original languageEnglish
Pages (from-to)713-720
Number of pages8
JournalAmerican Journal of Human Genetics
Volume87
Issue number5
DOIs
StatePublished - 12 Nov 2010

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