RT Journal Article
SR Electronic
T1 Genotype–phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 224
OP 235
DO 10.1136/jmedgenet-2016-103985
VO 54
IS 4
A1 Vito Terlizzi
A1 Giuseppe Castaldo
A1 Donatello Salvatore
A1 Marco Lucarelli
A1 Valeria Raia
A1 Adriano Angioni
A1 Vincenzo Carnovale
A1 Natalia Cirilli
A1 Rosaria Casciaro
A1 Carla Colombo
A1 Antonella Miriam Di Lullo
A1 Ausilia Elce
A1 Paola Iacotucci
A1 Marika Comegna
A1 Manuela Scorza
A1 Vincenzina Lucidi
A1 Anna Perfetti
A1 Roberta Cimino
A1 Serena Quattrucci
A1 Manuela Seia
A1 Valentina Maria Sofia
A1 Federica Zarrilli
A1 Felice Amato
YR 2017
UL http://jmg.bmj.com/content/54/4/224.abstract
AB Background The effect of complex alleles in cystic fibrosis (CF) is poorly defined for the lack of functional studies.Objectives To describe the genotype–phenotype correlation and the results of either in vitro and ex vivo studies performed on nasal epithelial cells (NEC) in a cohort of patients with CF carrying cystic fibrosis transmembrane conductance regulator (CFTR) complex alleles.Methods We studied 70 homozygous, compound heterozygous or heterozygous for CFTR mutations: p.[Arg74Trp;Val201Met;Asp1270Asn], n=8; p.[Ile148Thr;Ile1023_Val1024del], n=5; p.[Arg117Leu;Leu997Phe], n=6; c.[1210-34TG[12];1210-12T[5];2930C>T], n=3; p.[Arg74Trp;Asp1270Asn], n=4; p.Asp1270Asn, n=2; p.Ile148Thr, n=6; p.Leu997Phe, n=36. In 39 patients, we analysed the CFTR gating activity on NEC in comparison with patients with CF (n=8) and carriers (n=4). Finally, we analysed in vitro the p.[Arg74Trp;Val201Met;Asp1270Asn] complex allele.Results The p.[Ile148Thr;Ile1023_Val1024del] caused severe CF in five compound heterozygous with a class I–II mutation. Their CFTR activity on NEC was comparable with patients with two class I–II mutations (mean 7.3% vs 6.9%). The p.[Arg74Trp;Asp1270Asn] and the p.Asp1270Asn have scarce functional effects, while p.[Arg74Trp;Val201Met;Asp1270Asn] caused mild CF in four of five subjects carrying a class I–II mutation in trans, or CFTR-related disorders (CFTR-RD) in three having in trans a class IV–V mutation. The p.[Arg74Trp;Val201Met;Asp1270Asn] causes significantly (p<0.001) higher CFTR activity compared with compound heterozygous for class I–II mutations. Furthermore, five of six compounds heterozygous with the p.[Arg117Leu;Leu997Phe] had mild CF, whereas the p.Leu997Phe, in trans with a class I–II CFTR mutation, caused CFTR-RD or a healthy status (CFTR activity: 21.3–36.9%). Finally, compounds heterozygous for the c.[1210-34TG[12];1210-12T[5];2930C>T] and a class I–II mutation had mild CF or CFTR-RD (gating activity: 18.5–19.0%).Conclusions The effect of complex alleles partially depends on the mutation in trans. Although larger studies are necessary, the CFTR activity on NEC is a rapid contributory tool to classify patients with CFTR dysfunction.