The present study provides evidence that the p.Leu1077Pro is a relatively frequent mutation associated with a phenotype characterized by pathological sweat test, pancreatic insufficiency and pulmonary disease.
The p.Leu1077Pro mutation consists in a transition T to C at nucleotide position 3362 in exon 17b of CFTR cDNA that is responsible of change of Leucine (CTG) to Proline (CCG) at position 1077 of the protein. This mutation belongs to the III class CFTR mutations and produce a protein that is trafficked to the cell membrane but does not respond to cAMP stimulation [8].
Today it is well known that in 90% of patients there is a correlation between the general type of CFTR mutation and the phenotype. Specifically, patients who carry class I-III mutations on both alleles are associated with pancreatic exocrine insufficiency, whereas those carrying at least one class IV-VI CFTR mutation are pancreatic sufficient [3].
Nevertheless p.Leu1077Pro mutation, although belonging to the class III CFTR mutations, was classified by Bozon et al. [8] in one CF patient, carrying p.Phe508del on the other chromosome, as a mild genotype because of its associated pancreatic sufficiency. However, data from CFTR2 [9] seem to contradict what was claimed by Bozon et al. since in 78% of patients analyzed in this database there was pancreatic insufficiency.
Although Cystic Fibrosis is a monogenic disease there is a great clinical diversity among patients, even among those carrying the same mutations in the CFTR gene and the degree of organ involvement and the severity of the disease seem to be linked not only to the amount of functional CFTR and to organ’s sensitivity to CFTR dysfunction but also to the influence of both genetic background of patient and environmental factors [20, 21].
On this regard, the mutation p.Leu1077Pro is typical of Southern Italy, overall in Puglia, in which the prevalence is higher (1.9% among all mutations) than in the world (< 1%) [10].
In our Eastern Sicilian Cystic Fibrosis Centre its prevalence resulted even higher (3.6% of all mutations) compared to that of Puglia. The influence of ethnic groups of Mediterranean basin and Greek colonisation of Sicily from 750 BC could explain this difference that clinically translates into a greater mixture of genomes within the same territory.
Recently, some modifiers genes, inherited independently by mutations in the CFTR gene, have been involved in phenotype/genotype correlation. Some candidate genes are those involved in the immune response and inflammation, because their presence or absence could influence different responses from person to person against bacteria and viruses responsible for respiratory infection, or could modulate the affinity of Pseudomonas aeruginosa individual 's respiratory epithelium [22].
Among our patients, three out of four, who were born after 1998, were screened for CF. They had abnormal IRT values and for this reason the CF diagnosis was confirmed soon after birth by sweat test. All of them had a p.Phe508del/p.Leu1077Pro genotype.
In the fourth patient the diagnosis has been performed during infant age, at 4 months of age: the presence of recurrent respiratory and gastrointestinal symptoms were the main reasons to address the child to our Centre to evaluate sweat test which resulted pathological. She had a p.Asn1303Lys/p.Leu1077Pro genotype.
All 4 patients had a pancreatic insufficiency (PI) phenotype and this data, in disagreement with what is reported by Bozon et al. [8], confirm what is evident from CFTR2.
The presence of both pancreatic insufficiency and pathological sweat test seem to indicate that this mutation is responsible for a classical form of CF.
The older patient had several episodes of pneumonia, Pseudomonas Aeruginosa chronic lung colonization, disseminated bronchiectasis and a significant reduction of FEV1 and FVC suggesting a severe course of the respiratory disease.
In support of this hypothesis, the other three patients, even if they kept FEV1 and FVC values within normal range, had showed a few pulmonary exacerbations that we treated with oral or i.v. antibiotics. Moreover we found a chronic (in Patients n.1 and n.2) or episodic (in Patients n.3) colonization of Staphylococcus aureus, while the occurrence of Pseudomonas aeruginosa in the sputum was reported few times in patients n.1 and n.2. In addition, patient n.1 had showed recurrent episodes of rhinosinusitis.