What is the role of genetics in the etiology of hypercalciuria?

Updated: Apr 23, 2019
  • Author: Stephen W Leslie, MD, FACS; Chief Editor: Vecihi Batuman, MD, FASN  more...
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Molecular genetics and other research have indicated potential lines of future investigation into the nature of hypercalciuria. For example, dysregulation of the calcium-sensing receptor–claudin-14 axis, as well as polymorphism in the regulatory region controlling expression of the calcium-sensing–receptor gene, may contribute to increased calcium excretion. [14, 15] More than 60 activating mutations in the calcium-sensing receptor have been identified to cause autosomal dominant hypocalcemic hypercalciuria. [19]

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disorder caused by mutations in the tight junction proteins claudin-16 and claudin-19, which are encoded by the CLDN16 and CLDN19 genes, respectively. Over 60 mutations in CLDN16 have been described in FHHNC. The disorder is characterized by excessive urinary losses of magnesium and calcium, bilateral nephrocalcinosis, and progressive chronic renal failure. [20]

An interesting study in specially prepared transgenic mice suggests the possible importance of the gene CLCN5, which encodes ClC5 (a renal chloride channel located exclusively in the kidney), to the development of hypercalciuria. The transgenic mice were produced using an antisense ribozyme targeted against ClC5 so that these mice lacked ClC5 activity. [21] This mouse model is similar to Dent disease in humans, which is a rare, heritable X-linked disorder with reduced ClC5 activity that is characterized by absorptive hypercalciuria, nephrocalcinosis, nephrolithiasis, low ̶ molecular weight proteinuria, Fanconi syndrome, and renal failure. In Dent disease, the nephrolithiasis, hypercalciuria, and nephrocalcinosis are eliminated with a renal transplant from a healthy individual, confirming the renal cause of these problems. [21]

Other promising lines of research involve overexpression of vitamin D receptors and deficiencies in various renal tubular enzymes.


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