2136 applied chemical probes that can bind to the –SH group of cysteine. The function and role in human disease of selected claudin genes are summarized in Table 1. Familial hypomagnesemic hypercalciuria with nephrocalcinosis Familial hypomagnesemia hypercalciuria nephrocalcinosis (FHHNC) is the only monogenic renal syndrome so far ascribed to claudin gene mutations. It is a rare, autosomal recessive disorder characterized by renal Mg wasting, hypercalciuria, nephrocalcinosis, a trend toward renal Table 1 Selected claudin isoforms of known function Claudin isoforms Localization in the kidney [63] Permeability properties Bowman’s capsule Cation barrier [64] Proximal tubule and early Cation selective thin descending limb pore [21] Pediatr Nephrol (2011) 26:2133–2142 insufficiency and occasionally ocular abnormalities [24]. FHHNC was first reported in 1972 followed by several other reports from different parts of the world [24–32]. The onset of this syndrome is in early childhood [24–31]. Kari et al. reported that the mean age at first presentation ranged 0.1–3 years; however, the mean age at diagnosis ranged 0.5–12 years [26]. End-stage renal disease usually follows in the second to third decade of life [24]. Approximately 30–75% of patients reported in case series have required hemodialysis within a decade of diagnosis [31, 33]. Other types of primary renal Mg wasting condition are also recognized, including isolated renal Mg wasting, mitochon- drial cytopathy associated with renal Mg wasting, Gitelman Phenotypes of knockout/ transgenic mouse model Impaired epidermal barrier leading to dehydration and death [68] Impaired proximal tubule Na reabsorption [18] Normal development and morphology Maintains integrity of of blood vessel, no cerebral bleeding endothelial blood-brain or barrier [75] edema. Loosen blood–brain barrier [74] Renal NaCl wasting, chronic dehydration, secondary hyperaldosteronism and growth retardation [57] Severe neurological and reproductive deficit [78] CNS myelin and Sertoli cell tight junction [78] Claudin-1 Claudin-2 Claudin-3 Claudin-4 Claudin-5 Claudin-6 Claudin-7 Claudin-8 Claudin-10 Claudin-11 Claudin-12 Claudin-14 Claudin-16 Claudin-19 Biological role in human disease HCV entry into hepatocyte [66, 67] Upregulated in inflammatory bowel disease [68] Pro-neoplastic in many malignancies [69] Receptor for Clostridium perfringens enterotoxin [70, 71] HCV entry into hepatocyte [66, 67] Vitamin-D dependent intestinal Ca2+ absorption [79] Mutated in autosomal recessive deafness [80] Thin ascending limb to collecting duct Thin ascending limb and collecting duct Glomerulus, proximal tubule, thick ascending limb, distal tubule, collecting duct Distal thin descending limb, macular densa, distal tubule, collecting duct Distal thin descending limb, distal tubule, collecting duct From proximal tubule to collecting duct Proximal tubule, thick ascending limb Unknown Unknown Unknown Cation barrier [72] and anion selective pore [73] Anion barrier [55] Cation barrier [13] Variable splicing, either Anion pore or cation pore [76] Cation barrier [77] Unknown Collecting duct Cation barrier [48] Deafness [48]. Normal renal salt handling [49] Thin ascending limb and thick ascending limb Thin ascending limb and thick ascending limb Cation selective pore [39] Chronic renal wasting of Mg and Ca, Mutated in FHHNC [36, 37] nephrocalcinosis [38] Cation barrier [15], Chronic renal wasting of Mg and Ca, Mutated in FHHNC with anion barrier [39] nephrocalcinosis [81] ocular involvement [36, 37]