title: Mutations in RIPK4 cause the autosomal-recessive form of popliteal pterygium syndrome.
abstract: The autosomal-recessive form of popliteal pterygium syndrome, also known as Bartsocas-Papas syndrome, is a rare, but frequently lethal disorder characterized by marked popliteal pterygium associated with multiple congenital malformations. Using Affymetrix 250K SNP array genotyping and homozygosity mapping, we mapped this malformation syndrome to chromosomal region 21q22.3. Direct sequencing of RIPK4 (receptor-interacting serine/threonine kinase protein 4) showed a homozygous transversion (c.362T>A) that causes substitution of a conserved isoleucine with asparagine at amino acid position 121 (p.Ile121Asn) in the serine/threonine kinase domain of the protein. Additional pathogenic mutations-a homozygous transition (c.551C>T) that leads to a missense substitution (p.Thr184Ile) at a conserved position and a homozygous one base-pair insertion mutation (c.777_778insA) predicted to lead to a premature stop codon (p.Arg260ThrfsX14) within the kinase domain-were observed in two families. Molecular modeling of the kinase domain showed that both the Ile121 and Thr184 positions are critical for the protein's stability and kinase activity. Luciferase reporter assays also demonstrated that these mutations are critical for the catalytic activity of RIPK4. RIPK4 mediates activation of the nuclear factor-κB (NF-κB) signaling pathway and is required for keratinocyte differentiation and craniofacial and limb development. The phenotype of Ripk4(-/-) mice is consistent with the human phenotype presented herein. Additionally, the spectrum of malformations observed in the presented families is similar, but less severe than the conserved helix-loop-helix ubiquitous kinase (CHUK)-deficient human fetus phenotype; known as Cocoon syndrome; this similarity indicates that RIPK4 and CHUK might function via closely related pathways to promote keratinocyte differentiation and epithelial growth.
authors.affiliation: Department of Medical Biology, Karadeniz Technical University Faculty of Medicine, Trabzon, Turkey. ersankalay@hotmail.com
authors.forename: Ersan
authors.initials: E
authors.lastname: Kalay
authors.forename: Orhan
authors.initials: O
authors.lastname: Sezgin
authors.forename: Vasant
authors.initials: V
authors.lastname: Chellappa
authors.forename: Mehmet
authors.initials: M
authors.lastname: Mutlu
authors.forename: Heba
authors.initials: H
authors.lastname: Morsy
authors.forename: Hulya
authors.initials: H
authors.lastname: Kayserili
authors.forename: Elmar
authors.initials: E
authors.lastname: Kreiger
authors.forename: Aysegul
authors.initials: A
authors.lastname: Cansu
authors.forename: Bayram
authors.initials: B
authors.lastname: Toraman
authors.forename: Ebtesam Mohammed
authors.initials: EM
authors.lastname: Abdalla
authors.forename: Yakup
authors.initials: Y
authors.lastname: Aslan
authors.forename: Shiv
authors.initials: S
authors.lastname: Pillai
authors.forename: Nurten A
authors.initials: NA
authors.lastname: Akarsu
mesh_terms: D000293:Adolescent; D000818:Animals; D001483:Base Sequence; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011625:Pterygium / Q000151:congenital* / Q000235:genetics; D012868:Skin Abnormalities
chemical_list: D016328:NF-kappa B; C417187:RIPK4 protein, human; D017346:Protein Serine-Threonine Kinases; C430884:Ripk4 protein, mouse