CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes

Area of Science:

• Genetics
• Molecular Biology
• Medical Science

Background:

• Cystic Fibrosis (CF) genotype-phenotype correlations are complex due to variable expressivity and complex CFTR gene alleles.
• Specific CFTR mutations and their combinations can lead to a spectrum of clinical outcomes, complicating direct genotype-phenotype associations.

Purpose of the Study:

• To investigate the clinical significance of complex CFTR alleles involving p.Gly149Arg, p.Asp443Tyr, p.Gly576Ala, and p.Arg668Cys.
• To correlate specific CFTR mutations and complex alleles with CF phenotypes and CFTR-related disorders through epidemiological and functional analyses.

Main Methods:

• Collaborative genotype-phenotype correlation study across 153 patients with specific CFTR mutations.
• Epidemiological data collection and structure-function relationship investigations for single and complex CFTR mutants.
• Functional studies assessing CFTR maturation, processing, and chloride channel activity for identified mutations.

Main Results:

• The p.Gly149Arg mutation, particularly in a triple mutant context, was associated with classical CF.
• Sixty-four patients presented with isolated infertility, and seven healthy individuals carried severe mutations, but none with p.Gly149Arg.
• Functional studies revealed p.Gly149Arg causes severe misprocessing, p.Asp443Tyr moderately affects maturation, and p.Gly576Ala/p.Arg668Cys mildly impact chloride conductance.

Conclusions:

• p.Gly149Arg significantly contributes to the CF phenotype.
• CFTR alleles p.[Arg668Cys], p.[Gly576Ala;Arg668Cys], and p.[Asp443Tyr;Gly576Ala;Arg668Cys] are linked to CFTR-related disorders.
• Comprehensive genotype-phenotype and functional studies are essential for understanding CFTR mutation impact on clinical presentation.