X-linked hypercalciuric nephrolithiasis: Clinical syndromes and chloride channel mutations

Abstract

The recent discovery of a gene responsible for a particular form of hypercalciuric nephrolithiasis has created excitement because it promises to shed light on mechanisms involved in both calcium stone formation and renal epithelial function. The disease that I will refer to here as X-linked hypercalciuric nephrolithiasis (XLHN) has been the subject of some confusion owing to the fact that it has been described over the past five years by different groups using different names, all but one of them polysyllabic: “X-linked recessive nephrolithiasis with renal failure” in North America, “Dent’s disease” in the United Kingdom, “X-linked recessive hypophosphatemic rickets” in Italy, and “low-molecularweight proteinuria with hypercalciuria and nephrocalcinosis” in Japan. These syndromes differ in degree from each other, but common themes include proximal tubular reabsorptive failure, nephrolithiasis, nephrocalcinosis, progressive renal insufficiency, and in some cases rickets. The fact of mutations in the same gene in each of these syndromes has now established that they are phenotypic variants of a single disease and not separate entities. Clinical studies of these patients produced few clues as to the pathophysiology of the condition, and the gene responsible for this disease was identified through a positional cloning approach rather than through the study of logical candidate genes. The gene identified, CLCN5, was novel. Sequence homology suggested, and expression studies confirmed, that the gene product was a member of the CLC family of voltage-gated chloride channels. This was a surprise, since it is not immediately clear how mutations in such a chloride channel could explain the clinical findings in this disease. The physiology of the gene product, designated CLC-5, is at present only partly understood, and is the subject of active research. SYNDROMES OF X-LINKED HYPERCALCIURIC NEPHROLITHIASIS Four syndromes of X-linked hypercalciuric nephrolithiasis (XLHN) were reported independently, but mutations in the chloride channel gene CLCN5 have been identified in all four syndromes, justifying the view that these together represent a single disease. Table 1 summarizes the features of these syndromes as originally described. An understanding of these reports is valuable in that it emphasizes the range of phenotypes in this disease, and as an effort to clarify the relationships among what some might otherwise be tempted to consider as separate entities.