The promise and challenge of high throughput sequencing to discover genes involved in Medullary Sponge Kidney disease

Medullary sponge kidney (MSK) is a rare, developmental congenital disease characterized by diffuse ectasia or dilation of precalyceal collecting tubules. It is generally considered a sporadic disorder, but an apparently autosomal dominant inheritance has also been observed. The diagnosis of MSK is radiographic: typical pictures reveal collections of contrast medium in dilated papillary ducts, giving the appearance of a blush or linear striations in the mildest cases, or of bouquets of flowers when cystic dilation of the collecting ducts is seen. We previously described the association of MSK with mutations in ATP6V1B1 and ATP6V0A4, responsible of distal renal tubular acidosis (dRTA), a condition characterized by hypokalemia, hyperchloremic metabolic acidosis, nephrocalcinosis, nephrolithiasis, osteomalacia and rickets. In this disorder the α-intercalated cells in the collecting duct are unable to secrete H+ and to acidify urine. The aim of our study was to investigate, on the basis of family history and clinical presentation at various ages, the relationship between MSK and dRTA: we studied first the possible role of the B1 and a4 apical subunits of the H+ATPase pump (at present 8 patients show pathogenetic variations in these two subunits) and afterwards whether other genes could be causative of this condition. We investigated, by high throughput sequencing, 25 patients classified as having MSK and we studied, in addition to the role of the above mentioned genes, other genes encoding proteins expressed in the tubules and genes implicated in the collecting duct system development. We will show the results of this new pilot study.