Understanding the genotype to phenotype relationship is clearly complex, this was highlighted in the last decade by many genome wide association studies (GWAS) identifying regions of the human genome that were associated with the particular disease that they were studying but struggling to identify specific variants that were likely to be responsible for this association. I will first talk about how we have used protein structural modelling to analyse candidate nonsynonymous single nucleotide variants (nsSNV) identified by multiple GWAS investigating a range of diseases [1-3]. Our approach included the modelling of protein structure and functional sites, particularly ligand binding sites. Using this approach across these different studies we identified a few nsSNVs that were likely to have an effect ligand binding and were therefore strong candidates for causing the association with the phenotype.<br/><br/>In the second part of the talk I will focus on how we have applied similar approaches to the analyse of nsSNVs present in individuals with cystinuria. Cystinuria is an inherited disease that results in the formation of cystine stones in the kidney. Two genes (SLC7A9 and SLC3A1) that form a dimeric amino acid transporter are known to be largely responsible for the disease. Variants that cause the disease disrupt amino acid transport across the cell membrane, which leads to the accumulation of the relatively insoluble cystinine, leading to the formation of stones. In this project we have sequenced SLC7A9 and SLC3A1 in a cohort of patients from Guy’s Hopsital, London, UK [4]. Structural and bioinformatics analysis of the variants identified was performed with the aim of identifying 1) how they alter transporter function and 2) how severe any effect they have on transport be may be to causing cystinuria symptoms [2]. This analysis was linked with the known symptoms of patients in the cohort with the intention that linking specific mutations with disease severity will enable us to infer the likely severity of new patients presenting with cystinuria and subsequently tailor the treatment they receive [5,6].

Using structural modelling of functional sites to analyse genetic variation associated with disease

ACS Spring Meeting 2021

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