Exome sequence identifies RIPK4 as the Bartsocas-Papas syndrome locus

Karen Mitchell, James O'Sullivan, Caterina Missero, Ed Blair, Rose Richardson, Beverley Anderson, Dario Antonini, Jeffrey C Murray, Alan L Shanske, Brian C Schutte, Rose-Anne Romano, Satrajit Sinha, Sanjeev S Bhaskar, Graeme C M Black, Jill Dixon, Michael J Dixon

Research output: Contribution to journalArticlepeer-review


Pterygium syndromes are complex congenital disorders that encompass several distinct clinical conditions characterized by multiple skin webs affecting the flexural surfaces often accompanied by craniofacial anomalies. In severe forms, such as in the autosomal-recessive Bartsocas-Papas syndrome, early lethality is common, complicating the identification of causative mutations. Using exome sequencing in a consanguineous family, we identified the homozygous mutation c.1127C>A in exon 7 of RIPK4 that resulted in the introduction of the nonsense mutation p.Ser376X into the encoded ankyrin repeat-containing kinase, a protein that is essential for keratinocyte differentiation. Subsequently, we identified a second mutation in exon 2 of RIPK4 (c.242T>A) that resulted in the missense variant p.Ile81Asn in the kinase domain of the protein. We have further demonstrated that RIPK4 is a direct transcriptional target of the protein p63, a master regulator of stratified epithelial development, which acts as a nodal point in the cascade of molecular events that prevent pterygium syndromes. © 2012 The American Society of Human Genetics.
Original languageEnglish
Pages (from-to)69-75
Number of pages7
JournalAmerican Journal of Human Genetics
Issue number1
Publication statusPublished - 13 Jan 2012


  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Child
  • Cleft Lip/diagnosis
  • Cleft Palate/diagnosis
  • Consanguinity
  • Craniofacial Abnormalities/genetics
  • Exome
  • Exons
  • Genes, Recessive
  • Genetic Loci
  • Humans
  • Keratinocytes/metabolism
  • Male
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Phosphoproteins/metabolism
  • Protein-Serine-Threonine Kinases/genetics
  • Pterygium/congenital
  • Severity of Illness Index
  • Skin Abnormalities
  • Trans-Activators/metabolism
  • Transcription Factors/metabolism
  • Tumor Suppressor Proteins/metabolism


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