New era of cystic fibrosis: Full mutational analysis and personalized therapy

Table 1 Cystic fibrosis transmembrane conductance regulator mutation classes and cystic fibrosis personalized therapy.

Mutation class	Functional effect	Structural defect	Mutation-specific intervention	Personalized therapy
I	Defective protein synthesis (complete lack of protein production)	Nonsense mutations	Restore synthesis by suppressors of premature stop codons in-frame (read-through drugs)	Suppressor in phase 3 trials: Ataluren
		Frameshift mutations
		Severe splicing mutations
		Deletions or insertions (a common mechanism is the onset of premature stop codons)
II	Defective protein processing and/or trafficking (severe decrease of protein in the apical membrane due to processing and/or maturation defects)	Missense mutations Small deletions or insertions	Restore processing and trafficking by correctors (chemical, molecular, pharmacological chaperones) and combined approaches (corrector + potentiator)	Combined therapy to patients: Orkambi (the corrector Lumacaftor + the potentiator Ivacaftor)
III	Defective channel regulation and/or gating (impaired channel opening)	Missense mutations	Restore channel regulation and gating by potentiators	Potentiator to patients: Ivacaftor
		Small deletions or insertions
IV	Defective Cl- conductance (reduced Cl- transport through the channel)	Missense mutations	Restore the Cl- conductance by potentiators	Under evaluation
		Small deletions or insertions
V	Reduced mRNA synthesis (reduction of the wild type mRNA)	Partial splicing mutations Promoter mutations	Restore wild-type mRNA levels by correctors, potentiators and/or antisense oligonucleotides	Under evaluation
VI	Decreased protein stability in membrane or reduced ability of other channel regulation	Missense mutations	Restore stability and regulation ability by potentiators, stabilizers and/or suppressors of overdue stop codons in-frame	Under evaluation
		Nonsense mutations
		Frameshift mutations (a common mechanism is the onset of overdue stop codons because of mutations of the protein C-terminus)