Genotype-phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles

V. Terlizzi, G. Castaldo, Donatello Salvatore, M. Lucarelli, Valeria Raia, Adriano Angioni, V. Carnovale, Natalia Cirilli, Rosaria Casciaro, Carla Colombo, Antonella Miriam Di Lullo, Ausilia Elce, Paola Iacotucci, M. Comegna, Manuela Scorza, Vincenzina Lucidi, Anna Perfetti, Roberta Cimino, S. Quattrucci, Manuela SeiaValentina M. Sofia, Federica Zarrilli, Felice Amato

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
JournalJournal of Medical Genetics
DOIs
Publication statusAccepted/In press - Oct 13 2016

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Cystic Fibrosis Transmembrane Conductance Regulator
Genetic Association Studies
Cystic Fibrosis
Alleles
Mutation
Nose
Epithelial Cells

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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Genotype-phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles. / Terlizzi, V.; Castaldo, G.; Salvatore, Donatello; Lucarelli, M.; Raia, Valeria; Angioni, Adriano; Carnovale, V.; Cirilli, Natalia; Casciaro, Rosaria; Colombo, Carla; Di Lullo, Antonella Miriam; Elce, Ausilia; Iacotucci, Paola; Comegna, M.; Scorza, Manuela; Lucidi, Vincenzina; Perfetti, Anna; Cimino, Roberta; Quattrucci, S.; Seia, Manuela; Sofia, Valentina M.; Zarrilli, Federica; Amato, Felice.

In: Journal of Medical Genetics, 13.10.2016.

Research output: Contribution to journalArticle

Terlizzi, V, Castaldo, G, Salvatore, D, Lucarelli, M, Raia, V, Angioni, A, Carnovale, V, Cirilli, N, Casciaro, R, Colombo, C, Di Lullo, AM, Elce, A, Iacotucci, P, Comegna, M, Scorza, M, Lucidi, V, Perfetti, A, Cimino, R, Quattrucci, S, Seia, M, Sofia, VM, Zarrilli, F & Amato, F 2016, 'Genotype-phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles', Journal of Medical Genetics. https://doi.org/10.1136/jmedgenet-2016-103985
Terlizzi, V. ; Castaldo, G. ; Salvatore, Donatello ; Lucarelli, M. ; Raia, Valeria ; Angioni, Adriano ; Carnovale, V. ; Cirilli, Natalia ; Casciaro, Rosaria ; Colombo, Carla ; Di Lullo, Antonella Miriam ; Elce, Ausilia ; Iacotucci, Paola ; Comegna, M. ; Scorza, Manuela ; Lucidi, Vincenzina ; Perfetti, Anna ; Cimino, Roberta ; Quattrucci, S. ; Seia, Manuela ; Sofia, Valentina M. ; Zarrilli, Federica ; Amato, Felice. / Genotype-phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles. In: Journal of Medical Genetics. 2016.
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title = "Genotype-phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles",
abstract = "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.",
author = "V. Terlizzi and G. Castaldo and Donatello Salvatore and M. Lucarelli and Valeria Raia and Adriano Angioni and V. Carnovale and Natalia Cirilli and Rosaria Casciaro and Carla Colombo and {Di Lullo}, {Antonella Miriam} and Ausilia Elce and Paola Iacotucci and M. Comegna and Manuela Scorza and Vincenzina Lucidi and Anna Perfetti and Roberta Cimino and S. Quattrucci and Manuela Seia and Sofia, {Valentina M.} and Federica Zarrilli and Felice Amato",
year = "2016",
month = "10",
day = "13",
doi = "10.1136/jmedgenet-2016-103985",
language = "English",
journal = "Journal of Medical Genetics",
issn = "0022-2593",
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TY - JOUR

T1 - Genotype-phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles

AU - Terlizzi, V.

AU - Castaldo, G.

AU - Salvatore, Donatello

AU - Lucarelli, M.

AU - Raia, Valeria

AU - Angioni, Adriano

AU - Carnovale, V.

AU - Cirilli, Natalia

AU - Casciaro, Rosaria

AU - Colombo, Carla

AU - Di Lullo, Antonella Miriam

AU - Elce, Ausilia

AU - Iacotucci, Paola

AU - Comegna, M.

AU - Scorza, Manuela

AU - Lucidi, Vincenzina

AU - Perfetti, Anna

AU - Cimino, Roberta

AU - Quattrucci, S.

AU - Seia, Manuela

AU - Sofia, Valentina M.

AU - Zarrilli, Federica

AU - Amato, Felice

PY - 2016/10/13

Y1 - 2016/10/13

N2 - 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.

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.

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