Léon Mutesa1, Abul Kalam Azad2, Catherine Verhaeghe1, Karin Segers1, Jean-François Vanbellinghen1, Louis Ngendahayo3, Emmanuel Kamanzi Rusingiza4, Philippe Rutwaza Mutwa4, Stephen Rulisa4, Lucien Koulischer1, Jean-Jacques Cassiman2, Harry Cuppens2, Vincent Bours5. 1. Department of Human Genetics, Centre Hospitalier Universitaire-Sart-Tilman, Grappe Interdisciplinaire de Genoprotéomique Appliquée-Research, University of Liège, Liège, Belgium. 2. Department of Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium. 3. Department of Pathology, Centre Hospitalier Universitaire-Butare, National University of Rwanda, Butare, Rwanda. 4. Department of Pediatrics, Centre Hospitalier Universitaire-Kigali, National University of Rwanda, Kigali, Rwanda. 5. Department of Human Genetics, Centre Hospitalier Universitaire-Sart-Tilman, Grappe Interdisciplinaire de Genoprotéomique Appliquée-Research, University of Liège, Liège, Belgium. Electronic address: vbours@ulg.ac.be.
Abstract
BACKGROUND: The defect in chloride and sodium transport in cystic fibrosis (CF) patients is a consequence of CF transmembrane conductance regulator (CFTR) loss of function and an abnormal interaction between CFTR and the epithelial sodium channel (ENaC). A few patients were described with CF-like symptoms, a single CFTR mutation, and an ENaC mutation. METHODS: To study African patients with CF-like symptoms and to relate the disease to gene mutations of both CFTR and ENaC genes, we collected clinical data and DNA samples from 60 African patients with a CF phenotype. The CFTR gene was first analyzed in all patients by denaturing high-performance liquid chromatography followed by direct sequencing; whereas, the sodium channel non-voltage-gated 1 alpha (SCNN1A), sodium channel non-voltage-gated 1 beta (SCNN1B), and sodium channel non-voltage-gated 1 gamma (SCNN1G) subunits of the ENaC gene were analyzed by sequencing in the five patients who carried only one CF mutation. The frequency of all identified ENaC variants was established in a control group of 200 healthy individuals and in the 55 CF-like patients without any CFTR mutation. RESULTS: Three CFTR mutants, including one previously undescribed missense mutation (p.A204T), and a 5T/7T variant were identified in five patients. ENaC gene sequencing in these five patients detected the following eight ENaC variants: c.72T>C and p.V573I in SCNN1A; p.V348M, p.G442V, c.1473 + 28C>T, and p.T577T in SCNN1B; and p.S212S and c.1176 + 30G>C in SCNN1G. In the 55 CF-like patients without any CFTR mutation, we identified five of these eight ENaC variants, including the frequent p.G442V polymorphism, but we did not detect the presence of the p.V348M, p.T577T, and c.1176 + 30G>C ENaC variants. Moreover, these last three ENaC variants, p.V348M, p.T577T, and c.1176 + 30G>C, were not found in the control group. CONCLUSION: Our data suggest that CF-like syndrome in Africa could be associated with CFTR and ENaC mutations.
BACKGROUND: The defect in chloride and sodium transport in cystic fibrosis (CF) patients is a consequence of CF transmembrane conductance regulator (CFTR) loss of function and an abnormal interaction between CFTR and the epithelial sodium channel (ENaC). A few patients were described with CF-like symptoms, a single CFTR mutation, and an ENaC mutation. METHODS: To study African patients with CF-like symptoms and to relate the disease to gene mutations of both CFTR and ENaC genes, we collected clinical data and DNA samples from 60 African patients with a CF phenotype. The CFTR gene was first analyzed in all patients by denaturing high-performance liquid chromatography followed by direct sequencing; whereas, the sodium channel non-voltage-gated 1 alpha (SCNN1A), sodium channel non-voltage-gated 1 beta (SCNN1B), and sodium channel non-voltage-gated 1 gamma (SCNN1G) subunits of the ENaC gene were analyzed by sequencing in the five patients who carried only one CF mutation. The frequency of all identified ENaC variants was established in a control group of 200 healthy individuals and in the 55 CF-like patients without any CFTR mutation. RESULTS: Three CFTR mutants, including one previously undescribed missense mutation (p.A204T), and a 5T/7T variant were identified in five patients. ENaC gene sequencing in these five patients detected the following eight ENaC variants: c.72T>C and p.V573I in SCNN1A; p.V348M, p.G442V, c.1473 + 28C>T, and p.T577T in SCNN1B; and p.S212S and c.1176 + 30G>C in SCNN1G. In the 55 CF-like patients without any CFTR mutation, we identified five of these eight ENaC variants, including the frequent p.G442V polymorphism, but we did not detect the presence of the p.V348M, p.T577T, and c.1176 + 30G>C ENaC variants. Moreover, these last three ENaC variants, p.V348M, p.T577T, and c.1176 + 30G>C, were not found in the control group. CONCLUSION: Our data suggest that CF-like syndrome in Africa could be associated with CFTR and ENaC mutations.
Authors: Scott C Bell; Marcus A Mall; Hector Gutierrez; Milan Macek; Susan Madge; Jane C Davies; Pierre-Régis Burgel; Elizabeth Tullis; Claudio Castaños; Carlo Castellani; Catherine A Byrnes; Fiona Cathcart; Sanjay H Chotirmall; Rebecca Cosgriff; Irmgard Eichler; Isabelle Fajac; Christopher H Goss; Pavel Drevinek; Philip M Farrell; Anna M Gravelle; Trudy Havermans; Nicole Mayer-Hamblett; Nataliya Kashirskaya; Eitan Kerem; Joseph L Mathew; Edward F McKone; Lutz Naehrlich; Samya Z Nasr; Gabriela R Oates; Ciaran O'Neill; Ulrike Pypops; Karen S Raraigh; Steven M Rowe; Kevin W Southern; Sheila Sivam; Anne L Stephenson; Marco Zampoli; Felix Ratjen Journal: Lancet Respir Med Date: 2019-09-27 Impact factor: 30.700