Exome Sequence Identifies RIPK4 as the Bartsocas- Papas Syndrome Locus

• Published in: American journal of human genetics Vol. 90; no. 1; pp. 69 - 75
• Main Authors: Mitchell, Karen, O'Sullivan, James, Missero, Caterina, Blair, Ed, Richardson, Rose, Anderson, Beverley, Antonini, Dario, Murray, Jeffrey C., Shanske, Alan L., Schutte, Brian C., Romano, Rose-Anne, Sinha, Satrajit, Bhaskar, Sanjeev S., Black, Graeme C.M., Dixon, Jill, Dixon, Michael J.
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 13.01.2012; Cell Press; Elsevier
• Subjects: Amino Acid Sequence; Animals; Base Sequence; Biological and medical sciences; Child; Cleft Lip - diagnosis; Cleft Lip - genetics; Cleft Palate - diagnosis; Cleft Palate - genetics; Congenital diseases; Consanguinity; Craniofacial Abnormalities - genetics; Exome; Exons; Fundamental and applied biological sciences. Psychology; Gene expression; General aspects. Genetic counseling; Genes, Recessive; Genetic disorders; Genetic Loci; Genetic research; Genetics of eukaryotes. Biological and molecular evolution; Humans; Keratinocytes - metabolism; Male; Medical genetics; Medical sciences; Mice; Molecular and cellular biology; Molecular Sequence Data; Mutation; Phosphoproteins - metabolism; Protein Serine-Threonine Kinases - genetics; Proteins; Pterygium - congenital; Pterygium - diagnosis; Pterygium - genetics; Severity of Illness Index; Skin Abnormalities; Trans-Activators - metabolism; Transcription Factors - metabolism; Tumor Suppressor Proteins - metabolism; Human; Genetics; Bartsocas Papas syndrome; Locus
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2011.11.013

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.