Mutations in RIPK4 Cause the Autosomal-Recessive Form of Popliteal Pterygium Syndrome

Kalay, Ersan; Sezgın, Orhan; Chellappa, Vasant; Mutlu, Mehmet; Morsy, Heba; Kayserili, Hülya; Kreiger, Elmar; Cansu, Ayşegül; Toraman, Bayram; Abdalla, Ebtesam; Aslan, Yakup; Pillai, Shiv; Akarsu, Nurten

doi:10.1016/j.ajhg.2011.11.014

Cited by 87 publications

(115 citation statements)

References 54 publications

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“…This likely explains the intraoral and esophageal fusions and the partial attachment of the limbs to the body wall in RIPK4 − / − mice (Figures 3b, d and f). Similar to the hypoplastic external genitalia observed in humans affected by PPS, 8,9 the genital tubercle was lacking in RIPK4 − / − mice (Figures 3f and 4a). …”

Section: G H and I)supporting

confidence: 67%

“…10,11 In addition, IRF6 (interferon regulatory factor 6) and RIPK4 have been implicated in PPS. 8,9,12 We found that similar to IRF6 mutants, 10,11,13 RIPK4 − / − mice 1 have a defective skin barrier function and cleft palate, and RIPK4 − / − keratinocytes fail to differentiate in vitro. In Xenopus, we show that IRF6 controls RIPK4 expression and that RIPK4 can rescue developmental defects imposed by IRF6 dysfunction, thereby identifying a novel genetic interaction between IRF6 and RIPK4.…”

mentioning

confidence: 79%

“…To address the functional properties of RIPK4 mutants identified in BPS, 8,9 we cloned four of these mutants: one introducing a frameshift and premature stop codon in the kinase domain (hRIPK4ins777a), one introducing a stop at the end of the intermediate domain (hRIPK4S376X), and two missense mutants in the kinase domain (hRIPK4I121N and hRIPK4T184I) (Figure 5f). HaCaT cells were transduced with these Flag-tagged, dox-inducible hRIPK4 constructs together with an NF-κB reporter.…”

Section: G H and I)mentioning

confidence: 99%

“…The autosomal dominant form of PPS (MIM: 119500) is caused by mutations in the IRF6 gene, 12,29 whereas the autosomal-recessive form of PPS, also referred to as BPS (MIM: 263650), was linked to inactivating RIPK4 mutations. 8,9 Despite the strong resemblance of these two syndromes, 30 no molecular interconnection between IRF6 and RIPK4 was known.…”

Section: G H and I)mentioning

confidence: 99%

“…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). 8,9 Similar to RIPK4 − / − mice, BPS patients show epithelial fusions, skin webs at flexural surfaces, atresia of the oral cavity, syndactily and alopecia, and they die perinatally. Similar to RIPK4 − / − mice, transcription factor IRF6 − / − mice display fusion of the esophagus and defective epidermal differentiation.…”

mentioning

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: G H and I)supporting

confidence: 67%

mentioning

confidence: 79%

Section: G H and I)mentioning

confidence: 99%

Section: G H and I)mentioning

confidence: 99%

mentioning

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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Eyelids, Eyelashes, and Eyebrows

Wooten

Loukas

2016

Bergman's Comprehensive Encyclopedia of Human Anatomic Variation

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Exome Analysis in Clinical Practice: Expanding the Phenotype of Bartsocas–Papas Syndrome

Gripp

Ennis

Napoli

2013

American J of Med Genetics Pt A

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Exome analysis has had a dramatic impact on genetic research. We present the application of such newly generated information to patient care. The patient was a female, born with normal growth parameters to nonconsanguineous parents after an uneventful pregnancy. She had bilateral cleft lip/palate and ankyloblepharon. Sparse hair, dysplastic nails and hypohidrosis were subsequently noted. With exception of speech related issues, her development was normal. A clinical diagnosis of ankyloblepharon-ectodermal defects-cleft lip/palate or Hay-Wells syndrome resulted in TP63 sequence analysis. TP63 sequence and deletion/duplication analysis of all coding exons had a normal result, as did chromosome and SNP array analysis. Diagnostic exome analysis revealed a heterozygous nonsense mutation in KRT83 categorized as deleterious and associated with monilethrix. In addition, a homozygous missense variant of unknown clinical significance was reported in RIPK4. Using research based exome analysis, RIPK4 had just a few months prior been identified as pathogenic for Bartsocas-Papas syndrome. While the clinical diagnostic report implied the KRT83 mutation as a more likely cause for the patient's phenotype, clinical correlation, literature review and use of computerized mutation analysis programs allowed us to identify the homozygous RIPK4 (c.488G > A; p.Gly163Asp) mutation as the underlying pathogenic change. Consequently, we expand the phenotype of Bartsocas-Papas syndrome to an attenuated presentation resembling Hay-Wells syndrome, lacking lethality and pterygia. In contrast to the autosomal dominant Hay-Wells syndrome, Bartsocas-Papas syndrome is autosomal recessive, implying a 25% recurrence risk.

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Mutations in RIPK4 Cause the Autosomal-Recessive Form of Popliteal Pterygium Syndrome

Cited by 87 publications

References 54 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

Eyelids, Eyelashes, and Eyebrows

Exome Analysis in Clinical Practice: Expanding the Phenotype of Bartsocas–Papas Syndrome

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