Genetic analysis of Rwandan patients with cystic fibrosis-like symptoms: identification of novel cystic fibrosis transmembrane conductance regulator and epithelial sodium channel gene variants.
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.


CONCLUSIONS
Our data suggest that CF-like syndrome in Africa could be associated with CFTR and ENaC mutations.
Mutesa
Léon
L
Department of Human Genetics, Centre Hospitalier Universitaire-Sart-Tilman, Grappe Interdisciplinaire de Genoprotéomique Appliquée-Research, University of Liège, Liège, Belgium.
Azad
Abul Kalam
AK
Department of Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium.
Verhaeghe
Catherine
C
Department of Human Genetics, Centre Hospitalier Universitaire-Sart-Tilman, Grappe Interdisciplinaire de Genoprotéomique Appliquée-Research, University of Liège, Liège, Belgium.
Segers
Karin
K
Department of Human Genetics, Centre Hospitalier Universitaire-Sart-Tilman, Grappe Interdisciplinaire de Genoprotéomique Appliquée-Research, University of Liège, Liège, Belgium.
Vanbellinghen
Jean-François
JF
Department of Human Genetics, Centre Hospitalier Universitaire-Sart-Tilman, Grappe Interdisciplinaire de Genoprotéomique Appliquée-Research, University of Liège, Liège, Belgium.
Ngendahayo
Louis
L
Department of Pathology, Centre Hospitalier Universitaire-Butare, National University of Rwanda, Butare, Rwanda.
Rusingiza
Emmanuel Kamanzi
EK
Department of Pediatrics, Centre Hospitalier Universitaire-Kigali, National University of Rwanda, Kigali, Rwanda.
Mutwa
Philippe Rutwaza
PR
Department of Pediatrics, Centre Hospitalier Universitaire-Kigali, National University of Rwanda, Kigali, Rwanda.
Rulisa
Stephen
S
Department of Pediatrics, Centre Hospitalier Universitaire-Kigali, National University of Rwanda, Kigali, Rwanda.
Koulischer
Lucien
L
Department of Human Genetics, Centre Hospitalier Universitaire-Sart-Tilman, Grappe Interdisciplinaire de Genoprotéomique Appliquée-Research, University of Liège, Liège, Belgium.
Cassiman
Jean-Jacques
JJ
Department of Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium.
Cuppens
Harry
H
Department of Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium.
Bours
Vincent
V
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.
D000293:Adolescent; D044383:Black People / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D003550:Cystic Fibrosis / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D053503:Epithelial Sodium Channels / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D011110:Polymorphism, Genetic; D012432:Rwanda
D053503:Epithelial Sodium Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator