Abstract
Synonymous single nucleotide polymorphisms (sSNPs), which change a nucleotide, but not the encoded amino acid, are perceived as neutral to protein function and thus, classified as benign. We report a patient who was diagnosed with cystic fibrosis (CF) at an advanced age and presented very mild CF symptoms. The sequencing of the whole cystic fibrosis transmembrane conductance regulator (CFTR) gene locus revealed that the patient lacks known CF-causing mutations. We found a homozygous sSNP (c.1584G>A) at the end of exon 11 in the CFTR gene. Using sensitive molecular methods, we report that the c.1584G>A sSNP causes cognate exon skipping and retention of a sequence from the downstream intron, both of which, however, occur at a relatively low frequency. In addition, we found two other sSNPs (c.2562T>G (p.Thr854=) and c.4389G>A (p.Gln1463=)), for which the patient is also homozygous. These two sSNPs stabilize the CFTR protein expression, compensating, at least in part, for the c.1584G>A-triggered inefficient splicing. Our data highlight the importance of considering sSNPs when assessing the effect(s) of complex CFTR alleles. sSNPs may epistatically modulate mRNA and protein expression levels and consequently influence disease phenotype and progression.
Highlights
Genes directly linked to disease have been identified through nonsense or missense mutations, leading to nonfunctional protein [1]
These results suggest that the homozygous c.1584G>A synonymous single nucleotide polymorphisms (sSNPs) caused only marginal alterations of the global gene expression with no indication of the activated molecular stress response, which on a cellular-wide level corroborates the very mild cystic fibrosis (CF) phenotype of this patient
We analyzed the effect of sSNPs in a subject with a very mild atypical CF phenotype
Summary
Genes directly linked to disease have been identified through nonsense or missense mutations (i.e., mutations that introduce a premature stop codon or exchange an amino acid, respectively), leading to nonfunctional protein [1]. With patientderived material (colorectal organoids) and in in vitro cell culture models, we characterized the CFTR mRNA expression pattern and found that along with the full-length transcript, a minor fraction of the CFTR transcript underwent aberrant splicing, including both exon 11 skipping and intron 11 retention. This patient is homozygous for two other sSNPs, i.e., c.2562T>G and c.4389G>A, which enhance the CFTR protein expression, and likely counteracting the losses from the partially inefficient splicing
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