Associating mutations causing cystinuria with disease severity with the aim of providing precision medicine

Abstract

BackgroundCystinuria is an inherited disease that results in the formation of cystine stones in the kidney, which can have serious health complications. Two genes (SLC7A9 and SLC3A1) that form an amino acid transporter are known to be responsible for the disease. Variants that cause the disease disrupt amino acid transport across the cell membrane, leading to the build-up of relatively insoluble cystine, resulting in formation of stones. Assessing the effects of each mutation is critical in order to provide tailored treatment options for patients. We used various computational methods to assess the effects of cystinuria associated mutations, utilising information on protein function, evolutionary conservation and natural population variation of the two genes. We also analysed the ability of some methods to predict the phenotypes of individuals with cystinuria, based on their genotypes, and compared this to clinical data.ResultsUsing a literature search, we collated a set of 94 SLC3A1 and 58 SLC7A9 point mutations known to be associated with cystinuria. There are differences in sequence location, evolutionary conservation, allele frequency, and predicted effect on protein function between these mutations and other genetic variants of the same genes that occur in a large population. Structural analysis considered how these mutations might lead to cystinuria. For SLC7A9, many mutations swap hydrophobic amino acids for charged amino acids or vice versa, while others affect known functional sites. For SLC3A1, functional information is currently insufficient to make confident predictions but mutations often result in the loss of hydrogen bonds and largely appear to affect protein stability. Finally, we showed that computational predictions of mutation severity were significantly correlated with the disease phenotypes of patients from a clinical study, despite different methods disagreeing for some of their predictions.ConclusionsThe results of this study are promising and highlight the areas of research which must now be pursued to better understand how mutations in SLC3A1 and SLC7A9 cause cystinuria. The application of our approach to a larger data set is essential, but we have shown that computational methods could play an important role in designing more effective personalised treatment options for patients with cystinuria.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-017-3913-1) contains supplementary material, which is available to authorized users.

Cystinuria in a 13-Month-Old girl with absence of mutations in the SLC3A1 and SLC7A9 genes

“…[2] The recently published literature review on a set of 94 SLC3A1 and 58 SLC7A9 point mutations known to be associated with cystinuria has shown that there were differences in sequence location, evolutionary conservation, allele frequency, and predicted effect on protein function between these mutations and other genetic variants of the same genes that occur in a large population. [3] Interestingly, the case in question supports the few published anecdotal studies on the absence of mutations in many patients with cystinuria. Obaid et al found in their studied case series on Saudi patients with cystinuria that two out of eight patients had negative molecular testing.…”

Transport of L-Arginine Related Cardiovascular Risk Markers

“…Most mutations identified in cystinuria are missense mutations leading to the change of a single amino acid in the protein. The effect of these mutations can range from having no effect on protein function to loss of function [ 183 ]. It is estimated that approximately 99% of cationic amino acids are reabsorbed at the apical membrane of proximal kidney tubules [ 96 , 97 ], indicating that b 0,+ AT-rBAT mediated transport may have a considerable leverage on the homeostasis of cationic amino acids.…”

Adverse events associated with currently used medical treatments for cystinuria and treatment goals: results from a series of 442 patients in France

“…Based on cystine crystalluria analyses, we suggest for the first time that the target of urine specific gravity should be ≤ 1.005 and we confirm that patients should maintain urine pH > 7. 5…”

“…Cystinuria (OMIM 220100), a genetic defect of cystine tubular reabsorption, is responsible for 1% of nephrolithiasis cases in adults and between 8% and 10% of cases in children . Cystinuria is caused by mutations in SLC3A1 or SLC7A9 genes, encoding, respectively, for the subunits rBAT and b0, +AT of an amino acid transporter B0 . Because of the poor solubility of cystine at urine pH <7, cystinuria results in stone formation.…”