TY - JOUR
T1 - Autosomal recessive hyponatremia due to isolated salt wasting in sweat associated with a mutation in the active site of Carbonic Anhydrase 12
AU - Muhammad, Emad
AU - Leventhal, Neta
AU - Parvari, Galit
AU - Hanukoglu, Aaron
AU - Hanukoglu, Israel
AU - Chalifa-Caspi, Vered
AU - Feinstein, Yael
AU - Weinbrand, Jenny
AU - Jacoby, Harel
AU - Manor, Esther
AU - Nagar, Tal
AU - Beck, John C.
AU - Sheffield, Val C.
AU - Hershkovitz, Eli
AU - Parvari, Ruti
N1 - Funding Information:
Acknowledgments Grants or fellowships supporting the writing of the paper: the research was supported by grant 300000-5152 of the Chief Scientist of the Israeli Ministry of Health to RP and EH, and by a grant of the Chief Scientist of the Israel Ministry of Health to AH and IH.
PY - 2011/4
Y1 - 2011/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79953820888&partnerID=8YFLogxK
U2 - 10.1007/s00439-010-0930-4
DO - 10.1007/s00439-010-0930-4
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 21184099
AN - SCOPUS:79953820888
SN - 0340-6717
VL - 129
SP - 397
EP - 405
JO - Human Genetics
JF - Human Genetics
IS - 4
ER -