Part A CORE Study Rationale Sample Clauses

Part A CORE Study Rationale. It is not clear how different genotypic classes with distinct CFTR protein abnormalities and varying degrees of residual protein function impact the pathophysiology of CF lung disease. Each of the CFTR mutations (>1,900 described) result in different functional protein consequences, ranging from complete protein absence to defective protein activity at the plasma membrane. CFTR mutations are broadly categorized into five classes based on the molecular effect of the gene mutation on the CFTR protein function.1 Class I (nonsense mutations) include premature termination codons and frame shift mutations that result in either no significant protein synthesis or low levels of truncated CFTR proteins. Class II mutations, which includes the most common F508del mutant, cause folding or maturation defects, and little detectable CFTR at the plasma membrane. Class III mutations (e.g., G551D) lead to the formation of CFTR proteins which reach the plasma membrane but are nonfunctional secondary to gating defects that limit channel opening. As such, Class I-III mutations typically have minimal protein function and are associated with a classic CF phenotype including pancreatic insufficiency. Class IV and V mutations are associated with either reduced chloride conductance through the CFTR protein or reduced levels of the CFTR protein at the plasma membrane, respectively. Individuals with one Class IV or V mutation typically have residual CFTR function (i.e., partial function mutations), often have sufficient pancreatic function to absorb nutrients without supplemental pancreatic enzymes (i.e., pancreatic sufficiency), and may have sweat chloride values in the CF diagnostic or intermediate ranges.2 While underlying CFTR mutations are strong predictors of pancreatic status, mutation class is a relatively poor predictor of lung disease phenotype. It is thought that in addition to the CFTR genotype, CFTR independent factors including CF modifier genes and environmental factors influence the variability of CF lung disease and co- morbidities.3, 4 Part A of the study will focus on the clinical measures and molecular mediators that characterize different levels of CFTR activity (absent versus partial function) including a comparison to healthy control subjects in order to better understand the influence of CFTR function on phenotypic variability which may aid in the future evaluation of emerging CFTR modulator therapies for individuals with CF. Biomarker analysis of biospecimens...
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