caa a22 4500 445861630 CHVBK 20180317145445.0 cr unu---uuuuu 170323e20110401xx s 000 0 eng 10.1007/s00439-010-0930-4 doi (NATIONALLICENCE)springer-10.1007/s00439-010-0930-4 Autosomal recessive hyponatremia due to isolated salt wasting in sweat associated with a mutation in the active site of Carbonic Anhydrase 12 [Elektronische Daten] [Emad Muhammad, Neta Leventhal, Galit Parvari, Aaron Hanukoglu, Israel Hanukoglu, Vered Chalifa-Caspi, Yael Feinstein, Jenny Weinbrand, Harel Jacoby, Esther Manor, Tal Nagar, John Beck, Val Sheffield, Eli Hershkovitz, Ruti Parvari] Genetic disorders of excessive salt loss from sweat glands have been observed in pseudohypoaldosteronism type I (PHA) and cystic fibrosis that result from mutations in genes encoding epithelial Na+ channel (ENaC) subunits and the transmembrane conductance regulator (CFTR), respectively. We identified a novel autosomal recessive form of isolated salt wasting in sweat, which leads to severe infantile hyponatremic dehydration. Three affected individuals from a small Bedouin clan presented with failure to thrive, hyponatremic dehydration and hyperkalemia with isolated sweat salt wasting. Using positional cloning, we identified the association of a Glu143Lys mutation in carbonic anhydrase 12 (CA12) with the disease. Carbonic anhydrase is a zinc metalloenzyme that catalyzes the reversible hydration of carbon dioxide to form a bicarbonate anion and a proton. Glu143 in CA12 is essential for zinc coordination in this metalloenzyme and lowering of the protein-metal affinity reduces its catalytic activity. This is the first presentation of an isolated loss of salt from sweat gland mimicking PHA, associated with a mutation in the CA12 gene not previously implicated in human disorders. Our data demonstrate the importance of bicarbonate anion and proton production on salt concentration in sweat and its significance for sodium homeostasis. Springer-Verlag, 2010 Muhammad Emad Department of Virology and Developmental Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, 84105, Beer Sheva, Israel aut Leventhal Neta Pediatric Endocrinology and Metabolism Unit, Soroka Medical Center, 84101, Beer Sheva, Israel aut Parvari Galit Department of Organic and Inorganic Chemistry, Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, 32000, Haifa, Israel aut Hanukoglu Aaron Division of Pediatric Endocrinology, E Wolfson Medical Center, 58100, Holon, Israel aut Hanukoglu Israel Department of Molecular Biology, Ariel University Center, 40700, Ariel, Israel aut Chalifa-Caspi Vered National Institute of Biotechnology in the Negev, Ben Gurion University of the Negev, 84105, Beer Sheva, Israel aut Feinstein Yael Pediatric Endocrinology and Metabolism Unit, Soroka Medical Center, 84101, Beer Sheva, Israel aut Weinbrand Jenny Pediatric Endocrinology and Metabolism Unit, Soroka Medical Center, 84101, Beer Sheva, Israel aut Jacoby Harel Pediatric Endocrinology and Metabolism Unit, Soroka Medical Center, 84101, Beer Sheva, Israel aut Manor Esther Department of Virology and Developmental Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, 84105, Beer Sheva, Israel aut Nagar Tal National Institute of Biotechnology in the Negev, Ben Gurion University of the Negev, 84105, Beer Sheva, Israel aut Beck John Department of Pediatrics, Division of Medical Genetics, Howard Hughes Medical Institute, University of Iowa, IA 52242, Iowa City, USA aut Sheffield Val Department of Pediatrics, Division of Medical Genetics, Howard Hughes Medical Institute, University of Iowa, IA 52242, Iowa City, USA aut Hershkovitz Eli Pediatric Endocrinology and Metabolism Unit, Soroka Medical Center, 84101, Beer Sheva, Israel aut Parvari Ruti Department of Virology and Developmental Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, 84105, Beer Sheva, Israel aut Human Genetics Springer-Verlag 129/4(2011-04-01), 397-405 0340-6717 129:4<397 2011 129 439 https://doi.org/10.1007/s00439-010-0930-4 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00439-010-0930-4 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Muhammad Emad Department of Virology and Developmental Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, 84105, Beer Sheva, Israel aut NATIONALLICENCE 700 1- Leventhal Neta Pediatric Endocrinology and Metabolism Unit, Soroka Medical Center, 84101, Beer Sheva, Israel aut NATIONALLICENCE 700 1- Parvari Galit Department of Organic and Inorganic Chemistry, Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, 32000, Haifa, Israel aut NATIONALLICENCE 700 1- Hanukoglu Aaron Division of Pediatric Endocrinology, E Wolfson Medical Center, 58100, Holon, Israel aut NATIONALLICENCE 700 1- Hanukoglu Israel Department of Molecular Biology, Ariel University Center, 40700, Ariel, Israel aut NATIONALLICENCE 700 1- Chalifa-Caspi Vered National Institute of Biotechnology in the Negev, Ben Gurion University of the Negev, 84105, Beer Sheva, Israel aut NATIONALLICENCE 700 1- Feinstein Yael Pediatric Endocrinology and Metabolism Unit, Soroka Medical Center, 84101, Beer Sheva, Israel aut NATIONALLICENCE 700 1- Weinbrand Jenny Pediatric Endocrinology and Metabolism Unit, Soroka Medical Center, 84101, Beer Sheva, Israel aut NATIONALLICENCE 700 1- Jacoby Harel Pediatric Endocrinology and Metabolism Unit, Soroka Medical Center, 84101, Beer Sheva, Israel aut NATIONALLICENCE 700 1- Manor Esther Department of Virology and Developmental Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, 84105, Beer Sheva, Israel aut NATIONALLICENCE 700 1- Nagar Tal National Institute of Biotechnology in the Negev, Ben Gurion University of the Negev, 84105, Beer Sheva, Israel aut NATIONALLICENCE 700 1- Beck John Department of Pediatrics, Division of Medical Genetics, Howard Hughes Medical Institute, University of Iowa, IA 52242, Iowa City, USA aut NATIONALLICENCE 700 1- Sheffield Val Department of Pediatrics, Division of Medical Genetics, Howard Hughes Medical Institute, University of Iowa, IA 52242, Iowa City, USA aut NATIONALLICENCE 700 1- Hershkovitz Eli Pediatric Endocrinology and Metabolism Unit, Soroka Medical Center, 84101, Beer Sheva, Israel aut NATIONALLICENCE 700 1- Parvari Ruti Department of Virology and Developmental Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, 84105, Beer Sheva, Israel aut NATIONALLICENCE 773 0- Human Genetics Springer-Verlag 129/4(2011-04-01), 397-405 0340-6717 129:4<397 2011 129 439 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer