RIP4 Is an Ankyrin Repeat-Containing Kinase Essential for Keratinocyte Differentiation

Holland, Pamela M.; Willis, Cynthia R.; Kanaly, Suzanne; Glaccum, Moira; Warren, Annjanette S.; Charrier, K; Murison, J. Greg; Derry, Jonathan M.J.; Virca, G. Duke; Bird, Timothy A.; Peschon, Jacques J.

doi:10.1016/s0960-9822(02)01075-8

Cited by 94 publications

(130 citation statements)

References 29 publications

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“…In contrast to WT skin, the outermost epidermal cell layers are nucleated in RIPK4 − / − skin (Figures 1a and c). This phenotype was originally described as parakeratosis, 3 defined as keratinization with retention of nuclei. However, patches of anuclear corneocytes are found beneath the outermost nucleated cells (Figures 1a and c).…”

Section: Resultsmentioning

confidence: 99%

“…The most striking characteristic of RIPK4 − / − mice is the epithelial fusion of all external orifices and the esophagus, as well as the partial attachment of limbs to the body wall 3 ( Figures 3a-f), but it remains unclear how these fusions arise. When we analyzed different embryonic stages, we found that the mouth cavity is initially formed in E12.5 RIPK4 − / − embryos, but the epithelia lining the oral cavity fuse completely at E13.5 ( Supplementary Figures S2F and G).…”

Section: Resultsmentioning

confidence: 99%

“…2 Previous studies indicated that receptor-interacting protein kinase 4 (RIPK4) has a crucial role in epidermal differentiation and can participate in cutaneous inflammation. [3][4][5] RIPK4 is a member of the RIP serine/threonine kinase family, which act as integrators of stress signals leading to the activation of NF-κB, MAP kinases, cell death or inflammation. 6,7 All RIPKs contain a homologous kinase domain but have different protein-protein interaction domains allowing them to function in different pathways.…”

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confidence: 99%

“…3 However, the etiology of this phenotype remains unclear. As the outermost layer of the RIPK4 − / − epidermis is composed of flattened nucleated cells, it was presumed that the skin of these mice is parakeratotic.…”

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confidence: 99%

“…RIPK4 − / − mice also exhibit partial fusion of the limbs to the body, reduced skin folds and fusion of external orifices, including the nose, mouth and anus. 3 These mice die at birth because of their inability to breathe. RIPK4 was found to be mutated in humans affected by an autosomal-recessive form of popliteal pterygium syndrome (PPS), also known as Bartsocas-Papas syndrome (BPS).…”

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confidence: 99%

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A novel RIPK4–IRF6 connection is required to prevent epithelial fusions characteristic for popliteal pterygium syndromes

et al. 2014

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Receptor-interacting protein kinase 4 (RIPK4)-deficient mice have epidermal defects and fusion of all external orifices. These are similar to Bartsocas-Papas syndrome and popliteal pterygium syndrome (PPS) in humans, for which causative mutations have been documented in the RIPK4 and IRF6 (interferon regulatory factor 6) gene, respectively. Although genetically distinct, these syndromes share the anomalies of marked pterygia, syndactyly, clefting and hypoplastic genitalia. Despite the strong resemblance of these two syndromes, no molecular connection between the transcription factor IRF6 and the kinase RIPK4 was known and the mechanism underlying the phenotype was unclear. Here we describe that RIPK4 deficiency in mice causes epithelial fusions associated with abnormal periderm development and aberrant ectopic localization of E-cadherin on the apical membrane of the outer peridermal cell layers. In Xenopus, RIPK4 depletion causes the absence of ectodermal epiboly and concomitant gastrulation defects that phenocopy ectopic expression of dominant-negative IRF6. We found that IRF6 controls RIPK4 expression and that wild-type, but not kinase-dead, RIPK4 can complement the gastrulation defect in Xenopus caused by IRF6 malfunctioning. In contrast to the mouse, we observed only minor effects on cadherin membrane expression in Xenopus RIPK4 morphants. However, gastrulation defects were associated with a virtual absence of cortical actin in the ectodermal cells that face the blastocoel cavity and this was phenocopied in embryos expressing dominant-negative IRF6. A role for RIPK4 in actin cytoskeleton organization was also revealed in mouse epidermis and in human epithelial HaCaT cells. In conclusion, we showed that in mice RIPK4 is implicated in cortical actin organization and in E-cadherin localization or function, which can explain the characteristic epithelial fusions observed in PPSs. In addition, we provide a novel molecular link between IRF6 and RIPK4 that unifies the different PPSs to a common molecular pathway.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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A novel RIPK4–IRF6 connection is required to prevent epithelial fusions characteristic for popliteal pterygium syndromes

et al. 2014

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Expanding the genetic and phenotypic spectrum of popliteal pterygium disorders

Leslie

O’Sullivan

Cunningham

et al. 2015

American J of Med Genetics Pt A

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The popliteal pterygia syndromes are a distinct subset of the hundreds of Mendelian orofacial clefting syndromes. Popliteal pterygia syndromes have considerable variability in severity and in the associated phenotypic features but are all characterized by cutaneous webbing across one or more major joints, cleft lip and/or palate, syndactyly, and genital malformations. Heterozygous mutations in IRF6 cause popliteal pterygium syndrome (PPS) while homozygous mutations in RIPK4 or CHUK (IKKA) cause the more severe Bartsocas-Papas syndrome (BPS) and Cocoon syndrome, respectively. In this study we report mutations in six pedigrees with children affected with PPS or BPS. Using a combination of Sanger and exome sequencing, we report the first case of an autosomal recessive popliteal pterygium syndrome caused by homozygous mutation of IRF6 and the first case of uniparental disomy of chromosome 21 leading to a recessive disorder. We also demonstrate that mutations in RIPK4 can cause features with a range of severity along the PPS-BPS spectrum and that mutations in IKKA can cause a range of features along the BPS-Cocoon spectrum. Our findings have clinical implications for genetic counseling of families with pterygia syndromes and further implicate IRF6, RIPK4, and CHUK (IKKA) in potentially interconnected pathways governing epidermal and craniofacial development.

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Identification of a novel mutation in RIPK4 in a kindred with phenotypic features of Bartsocas‐Papas and CHAND syndromes

Gollasch

Basmanav

Nanda

et al. 2015

American J of Med Genetics Pt A

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Three children from an expanded consanguineous Kuwaiti kindred presented with ankyloblepharon, sparse and curly hair, and hypoplastic nails, suggestive of CHAND syndrome (OMIM 214350) that belongs to the heterogeneous spectrum of ectodermal dysplasias. After exclusion of pathogenic mutations in TP63 we performed homozygosity mapping, followed by exome sequencing of one affected individual. We initially identified three homozygous mutations in the linked region, located in PWP2, MX2 and RIPK4. Recently, mutations in RIPK4 have been reported in Bartsocas-Papas syndrome (OMIM 263650) that shows overlapping clinical symptoms with the phenotype observed in the affected individuals studied here. Subsequent analysis of affected and non-affected family members showed that mutation c.850G>A (p.Glu284Lys) in RIPK4 was in complete segregation with the disease phenotype, in accordance with an autosomal recessive inheritance pattern, thus supporting pathogenicity of this variant. Interestingly, however, our patients did not have cleft lip/palate, a common feature encountered in Bartsocas-Papas syndrome. Whereas in Bartsocas-Papas syndromes missense mutations are usually located within the serin/threonin kinase of RIPK4, the mutation detected in our family resides just outside of the kinase domain, which could explain the milder phenotype. Our data raise the question if CHAND syndrome indeed is a distinct entity. Alternatively, CHAND and Bartsocas-Papas syndrome might be allelic disorders or RIPK4 mutations could confer varying degrees of phenotypic severity, depending on their localization within or outside functionally important domains. Our findings indicate that making an accurate diagnosis based only on the prevailing clinical symptoms is challenging.

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RIP4 Is an Ankyrin Repeat-Containing Kinase Essential for Keratinocyte Differentiation

Cited by 94 publications

References 29 publications

A novel RIPK4–IRF6 connection is required to prevent epithelial fusions characteristic for popliteal pterygium syndromes

A novel RIPK4–IRF6 connection is required to prevent epithelial fusions characteristic for popliteal pterygium syndromes

Expanding the genetic and phenotypic spectrum of popliteal pterygium disorders

Identification of a novel mutation in RIPK4 in a kindred with phenotypic features of Bartsocas‐Papas and CHAND syndromes

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