title: A novel missense mutation in the transcription factor FOXF1 cosegregating with infantile hypertrophic pyloric stenosis in the extended pedigree linked to IHPS5 on chromosome 16q24.
abstract: BACKGROUND
  The aim was to identify susceptibility alleles for infantile hypertrophic pyloric stenosis (IHPS) in a pedigree previously linked to IHPS5 on chromosome 16q24.
  
  
  METHODS
  We screened the positional and functional candidate gene FOXF1 by Sanger sequencing in a single affected individual. All family members for whom DNA was available were genotyped to determine cosegregation status of the putative causal variant. Immunofluorescence studies were performed to compare the cellular localization of wildtype and mutant form of the protein. Transcriptional activity was compared using a luciferase assay.
  
  
  RESULTS
  A single novel substitution in FOXF1 (c.416G>A) predicted to result in a missense mutation (R139Q) was shown to cosegregate with disease trait. It was not seen in 560 control chromosomes nor has it been reported in ExAC or ESP. The R139Q substitution affects a conserved arginine residue within the DNA-binding domain of FOXF1. The transcriptional activity of the mutant FOXF1 protein is significantly reduced in comparison to wild-type.
  
  
  CONCLUSIONS
  These results provide strong evidence that the R139Q substitution in FOXF1 causes IHPS in this family and imply a novel pathological pathway for the condition. They further support a role for FOXF1 in the regulation of embryonic and neonatal development of the gastro-intestinal tract.
authors.affiliation: Cell Biology and Genetics Research Centre, St George's University of London, London, UK.
authors.forename: Kate V
authors.initials: KV
authors.lastname: Everett
authors.affiliation: Cell Biology and Genetics Research Centre, St George's University of London, London, UK.
authors.forename: Paris
authors.initials: P
authors.lastname: Ataliotis
authors.affiliation: University of Exeter Medical School, Exeter, UK.
authors.forename: Barry A
authors.initials: BA
authors.lastname: Chioza
authors.affiliation: Peninsula College of Medicine and Dentistry, Universities of Exeter and Plymouth, Exeter, UK.
authors.forename: Charles
authors.initials: C
authors.lastname: Shaw-Smith
authors.affiliation: Institute of Child Health, University College London, London, UK.
authors.forename: Eddie M K
authors.initials: EMK
authors.lastname: Chung
mesh_terms: D000483:Alleles; D001120:Arginine / Q000737:chemistry; D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D057809:HEK293 Cells; D006239:Haplotypes; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence; D020125:Mutation, Missense; D010375:Pedigree; D046248:Pyloric Stenosis, Hypertrophic / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015533:Transcriptional Activation
chemical_list: C098521:FOXF1 protein, human; C491001:FOXL1 protein, human; D051858:Forkhead Transcription Factors; C082078:mesenchyme fork head 1 protein; D001120:Arginine