Introduction
Cystic fibrosis (CF), which is one of the most common autosomal
recessive diseases in Caucasian populations caused by mutations in the
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. The
gene encodes for an ion channel located in the apical membrane of
epithelial cells which transports chloride ions and
bicarbonate.1 To date, over 2000 mutations have been
reported in the CFTR gene. Mutations have been classified into seven
groups that affect the production of CFTR protein (Class IA and IB), its
trafficking (Class II), its conductance (Class III and Class IV), its
function (Class V) and its stability (Class VI)2.
Although CF is characterized by chronic progressive lung disease it also
affects sweat glands, liver, pancreas, upper airway, intestine and
reproductive systems.3
Especially Pseudomonas aeruginosa and Staphlyococcus
aureus cause chronic lung infection in patients and lung disease is the
primary reason for mortality and morbidity in CF4,5.
As a result of defective CFTR protein in the pancreas approximately
60-80% of patients have exocrine pancreatic
insufficiency6,7. Additionally, dysfunction in the
pancreas causes CF-related diabetes (CFRD)8. On the
other hand, CFTR protein is necessary for the stability of mucus acidity
and hydration in the intestine and regulation of bile secretion in the
liver.9 Meconium ileus occurs in approximately 5-20%,
CF liver disease (CFLD) occurs in 5%-10% of
patients.9,10 Another affected system in CF is the
reproductive system. CF patients with mild CFTR mutations have been
shown to be associated with congenital bilateral absence of vas deferens
(CBAVD).11,12
Since CF is described as a multisystem disorder it is difficult to
establish genotype-phenotype correlation. Interestingly, some studies
have found that patients with the same genotype demonstrated variable
disease severity.13,14,15 Especially studies conducted
on twins and siblings with the same CFTR mutation but different clinical
symptoms, suggested that CF-related genes and genes that interact with
CFTR protein may play a role in clinical
heterogeneity.16,17 In recent years, there have been
transcriptomic approaches in order to characterize phenotypic
variability comparing CF patients to healthy controls or mild to severe
CF patients with the same CFTR mutation.18,19 However,
there is no transcriptomic study that includes mild and severe siblings
from families where families share the same genetic origin. In the
present study, we performed targeted transcriptomic analysis to identify
differentially expressed genes and associated molecular pathways between
mild and severe siblings.