title: Autosomal recessive hyponatremia due to isolated salt wasting in sweat associated with a mutation in the active site of Carbonic Anhydrase 12.
abstract: 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.
authors.affiliation: Department of Virology and Developmental Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, 84105, Israel.
authors.forename: Emad
authors.initials: E
authors.lastname: Muhammad
authors.forename: Neta
authors.initials: N
authors.lastname: Leventhal
authors.forename: Galit
authors.initials: G
authors.lastname: Parvari
authors.forename: Aaron
authors.initials: A
authors.lastname: Hanukoglu
authors.forename: Israel
authors.initials: I
authors.lastname: Hanukoglu
authors.forename: Vered
authors.initials: V
authors.lastname: Chalifa-Caspi
authors.forename: Yael
authors.initials: Y
authors.lastname: Feinstein
authors.forename: Jenny
authors.initials: J
authors.lastname: Weinbrand
authors.forename: Harel
authors.initials: H
authors.lastname: Jacoby
authors.forename: Esther
authors.initials: E
authors.lastname: Manor
authors.forename: Tal
authors.initials: T
authors.lastname: Nagar
authors.forename: John C
authors.initials: JC
authors.lastname: Beck
authors.forename: Val C
authors.initials: VC
authors.lastname: Sheffield
authors.forename: Eli
authors.initials: E
authors.lastname: Hershkovitz
authors.forename: Ruti
authors.initials: R
authors.lastname: Parvari
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000235:genetics*; D020134:Catalytic Domain / Q000235:genetics; D002712:Chlorides / Q000032:analysis; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D007010:Hyponatremia / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013542:Sweat / Q000737:chemistry
chemical_list: D002712:Chlorides; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII