The relative frequency of CFTR mutation classes in European patients with cystic fibrosis

Abstract

More than 1900 different mutations in the CFTR gene have been reported. These are grouped into classes according to their effect on the synthesis and/or function of the CFTR protein. CFTR repair therapies that are mutation or mutation class specific are under development. To progress efficiently in the clinical phase of drug development, knowledge of the relative frequency of CFTR mutation classes in different populations is useful. Therefore, we describe the mutation class spectrum in 25,394 subjects with CF from 23 European countries. In 18/23 countries, 80% or more of the patients had at least one class II mutation, explained by F508del being by far the most frequent mutation. Overall 16.4% of European patients had at least one class I mutation but this varied from 3 countries with more than 30% to 4 countries with less than 10% of subjects. Overall only respectively 3.9, 3.3 and 3.0% of European subjects had at least one mutation of classes III, IV and V with again great variability: 14% of Irish patients had at least one class III mutation, 7% of Portuguese patients had at least one class IV mutation, and in 6 countries more than 5% of patients had at least one class V mutation.

Role of CFTR in epithelial physiology

“…As stated in Chapter “Cystic Fibrosis: a clinical view”, CF is the most common genetically inherited disease in Caucasian populations (1 in 3500 newborns in Europe) [13, 14] and 70–90 % of CF individuals harbour the F508del mutation on at least one allele [15], which results in misfolding and incorrect processing of CFTR to the apical membrane. One of the first symptoms associated with CF, and occurring in around 17 % of CF patients, is meconium ileus; an obstruction of the bowel due to thick meconium and 98 % of babies with meconium ileus has CF.…”

Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation

“…Other mutations that reduce CFTR channel gating include G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, and G1349D; however, these mutations are very rare, jointly accounting for approximately 1% of patients with CF [2]. As for many other CFTR mutations, large regional differences in the occurrence of these mutations have been documented [7].…”

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

“…For example, long QT syndrome, a delay in cardiac ventricular repolarization, can be caused by mutations in several different voltage-gated ion channel genes, including potassium channel genes KCNQ1, KCNH2, KCNJ2, sodium channel gene SCN5A, and calcium channel gene CACNA1C (Campuzano et al, 2010). Most instances of cystic fibrosis can be attributed to one of five cystic fibrosis transmembrane conductance regulator classes of mutations, yet a myriad of disease-related mutations have been reported (De Boeck et al, 2014). Mutations in another ABC transporter (ABCC8) can cause three diseases: familial hyperinsulemic hypoglycemia and two forms of neonatal diabetes (Aittoniemi et al, 2009).…”