title: Exome sequence identifies RIPK4 as the Bartsocas-Papas syndrome locus.
abstract: 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.
authors.affiliation: Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Mitchell
authors.forename: James
authors.initials: J
authors.lastname: O'Sullivan
authors.forename: Caterina
authors.initials: C
authors.lastname: Missero
authors.forename: Ed
authors.initials: E
authors.lastname: Blair
authors.forename: Rose
authors.initials: R
authors.lastname: Richardson
authors.forename: Beverley
authors.initials: B
authors.lastname: Anderson
authors.forename: Dario
authors.initials: D
authors.lastname: Antonini
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
authors.forename: Alan L
authors.initials: AL
authors.lastname: Shanske
authors.forename: Brian C
authors.initials: BC
authors.lastname: Schutte
authors.forename: Rose-Anne
authors.initials: RA
authors.lastname: Romano
authors.forename: Satrajit
authors.initials: S
authors.lastname: Sinha
authors.forename: Sanjeev S
authors.initials: SS
authors.lastname: Bhaskar
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Black
authors.forename: Jill
authors.initials: J
authors.lastname: Dixon
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dixon
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002648:Child; D002971:Cleft Lip / Q000175:diagnosis / Q000235:genetics*; D002972:Cleft Palate / Q000175:diagnosis / Q000235:genetics*; D003241:Consanguinity; D019465:Craniofacial Abnormalities / Q000235:genetics; D059472:Exome; D005091:Exons; D005808:Genes, Recessive; D056426:Genetic Loci; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011625:Pterygium / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics; D012720:Severity of Illness Index; D012868:Skin Abnormalities; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D010750:Phosphoproteins; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C486419:Trp63 protein, mouse; D025521:Tumor Suppressor Proteins; C417187:RIPK4 protein, human; D017346:Protein Serine-Threonine Kinases; C430884:Ripk4 protein, mouse