title: Five novel mutations in the SCNN1A gene causing autosomal recessive pseudohypoaldosteronism type 1.
abstract: BACKGROUND
  Pseudohypoaldosteronism type 1 (PHA1) is a monogenic disease caused by mutations in the genes encoding the human mineralocorticoid receptor (MR) or the α (SCNN1A), β (SCNN1B) or γ (SCNN1G) subunit of the epithelial Na(+) channel (ENaC). While autosomal dominant mutation of the MR cause renal PHA1, autosomal recessive mutations of the ENaC lead to systemic PHA1. In the latter, affected children suffer from neonatal onset of multi-organ salt loss and often exhibit cystic fibrosis-like pulmonary symptoms.
  
  
  OBJECTIVE
  We searched for underlying mutations in seven unrelated children with systemic PHA1, all offsprings of healthy consanguineous parents.
  
  
  RESULTS
  Amplification of the SCNN1A gene and sequencing of all 13 coding exons unraveled mutations in all of our patients. We found five novel homozygous mutations (c.587_588insC in two patients, c.1342_1343insTACA, c.742delG, c.189C>A, c.1361-2A>G) and one known mutation (c.1474C>T) leading to truncation of the αENaC protein. All parents were asymptomatic heterozygous carriers of the respective mutations, confirming the autosomal recessive mode of inheritance. Five out of seven patients exhibited pulmonary symptoms in the neonatal period.
  
  
  CONCLUSIONS
  The α subunit is essential for ENaC function and mutations truncating the pore-forming part of the protein leading to systemic PHA1. Based on current knowledge, the pulmonary phenotype cannot be satisfactorily predicted.
authors: Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University Hospital Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany. m.welzel@pediatrics.uni-kiel.de
authors: Maik
authors: M
authors: Welzel
authors: Leyla
authors: L
authors: Akin
authors: Anja
authors: A
authors: Büscher
authors: Tülay
authors: T
authors: Güran
authors: Berthold P
authors: BP
authors: Hauffa
authors: Wolfgang
authors: W
authors: Högler
authors: Julia
authors: J
authors: Leonards
authors: Beate
authors: B
authors: Karges
authors: Heiner
authors: H
authors: Kentrup
authors: Birgul
authors: B
authors: Kirel
authors: Emine Esin Yalinbas
authors: EE
authors: Senses
authors: Neslihan
authors: N
authors: Tekin
authors: Paul-Martin
authors: PM
authors: Holterhus
authors: Felix G
authors: FG
authors: Riepe
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D053503:Epithelial Sodium Channels / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011546:Pseudohypoaldosteronism / Q000235:genetics* / Q000503:physiopathology
chemical_list: D053503:Epithelial Sodium Channels; C507045:SCNN1A protein, human