Department of Virology and Developmental Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, 84105, Israel.
Hum Genet. 2011 Apr;129(4):397-405. doi: 10.1007/s00439-010-0930-4. Epub 2010 Dec 24.
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.
已在假性醛固酮减少症 I 型（PHA）和囊性纤维化中观察到由于编码上皮钠通道（ENaC）亚基和跨膜电导调节剂（CFTR）的基因突变而导致的过度出汗的遗传性盐丢失障碍。我们鉴定了一种新型的孤立性汗盐丢失的常染色体隐性形式，导致严重的婴儿低钠性脱水。来自一个小型贝都因部落的 3 名受影响个体表现为生长不良、低钠性脱水和高钾血症伴孤立性汗盐丢失。通过定位克隆，我们鉴定出碳酸酐酶 12（CA12）的 Glu143Lys 突变与该疾病相关。碳酸酐酶是一种锌金属酶，可催化二氧化碳的可逆水合作用，形成碳酸氢根阴离子和质子。CA12 中的 Glu143 对于该金属酶中的锌配位至关重要，降低蛋白质 - 金属亲和力会降低其催化活性。这是首例模仿 PHA 的孤立性汗盐丢失的表现，与以前未涉及人类疾病的 CA12 基因突变相关。我们的数据表明，碳酸氢根阴离子和质子生成对汗盐浓度及其对钠稳态的重要性。
