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A Proteomic Variant Approach (ProVarA) for Personalized Medicine of Inherited and Somatic Disease

Author:
Hutt, Darren M., Loguercio, Salvatore, Campos, Alexandre Rosa, Balch, William E.
Source:
Journal of molecular biology 2018 v.430 no.18 pp. 2951-2973
ISSN:
0022-2836
Subject:
cystic fibrosis, disease control, etiology, genes, genomics, genotype, mass spectrometry, patients, phenotypic variation, precision medicine, proteomics, somatic mutation
Abstract:
The advent of precision medicine for genetic diseases has been hampered by the large number of variants that cause familial and somatic disease, a complexity that is further confounded by the impact of genetic modifiers. To begin to understand differences in onset, progression and therapeutic response that exist among disease-causing variants, we present the proteomic variant approach (ProVarA), a proteomic method that integrates mass spectrometry with genomic tools to dissect the etiology of disease. To illustrate its value, we examined the impact of variation in cystic fibrosis (CF), where 2025 disease-associated mutations in the CF transmembrane conductance regulator (CFTR) gene have been annotated and where individual genotypes exhibit phenotypic heterogeneity and response to therapeutic intervention. A comparative analysis of variant-specific proteomics allows us to identify a number of protein interactions contributing to the basic defects associated with F508del- and G551D-CFTR, two of the most common disease-associated variants in the patient population. We demonstrate that a number of these causal interactions are significantly altered in response to treatment with Vx809 and Vx770, small-molecule therapeutics that respectively target the F508del and G551D variants. ProVarA represents the first comparative proteomic analysis among multiple disease-causing mutations, thereby providing a methodological approach that provides a significant advancement to existing proteomic efforts in understanding the impact of variation in CF disease. We posit that the implementation of ProVarA for any familial or somatic mutation will provide a substantial increase in the knowledge base needed to implement a precision medicine-based approach for clinical management of disease.
Agid:
6128913