Cystinuria: an inborn cause of urolithiasis

Abstract

Cystinuria (OMIM 220100) is an inborn congenital disorder characterised by a defective cystine metabolism resulting in the formation of cystine stones. Among the heterogeneous group of kidney stone diseases, cystinuria is the only disorder which is exclusively caused by gene mutations. So far, two genes responsible for cystinuria have been identified: SLC3A1 (chromosome 2p21) encodes the heavy subunit rBAT of a renal b(0,+) transporter while SLC7A9 (chromosome 19q12) encodes its interacting light subunit b(0,+)AT. Mutations in SLC3A1 are generally associated with an autosomal-recessive mode of inheritance whereas SLC7A9 variants result in a broad clinical variability even within the same family. The detection rate for mutations in these genes is larger than 85%, but it is influenced by the ethnic origin of a patient and the pathophysiological significance of the mutations. In addition to isolated cystinuria, patients suffering from the hypotonia-cystinuria syndrome have been reported carrying deletions including at least the SLC3A1 and the PREPL genes in 2p21. By extensive molecular screening studies in large cohort of patients a broad spectrum of mutations could be identified, several of these variants were functionally analysed and thereby allowed insights in the pathology of the disease as well as in the renal trafficking of cystine and the dibasic amino acids. In our review we will summarize the current knowledge on the physiological and the genetic basis of cystinuria as an inborn cause of kidney stones, and the application of this knowledge in genetic testing strategies.

Figure 1

Cellular localisation and function of rBAT (SLC3A1) and b^0,+AT (SLC7A9).

Figure 2

Genomic structure and putative function of the encoded protein regions of the cystinuria genes: the total number of mutations described so far for each exon is shown above, the localisation of the most frequent mutations is shown below the exon structure.a)SLC3A1/rBAT (TMD transmembrane domain; the largest part of the protein consists of an ectodomain (light brown) of three domains A-C, for further details see [4]). b)SLC7A9/b^0,+AT (TMD transmembrane domain).