Popliteal pterygium syndrome. Evidence for a severe autosomal recessive form.

Bartsocas, Christos S.; Papas, C V

doi:10.1136/jmg.9.2.222

Cited by 81 publications

(44 citation statements)

References 10 publications

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“…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%

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)mentioning

confidence: 99%

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

et al. 2014

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“…Mutations in RIPK4 have been identified recently in BartsocasPapas syndrome (BPS) 3 (19,20). BPS is a more severe form of popliteal pterygium and causes death early in life (21,22). RIPK4 and IRF6 mutations have also been identified in squamous cell carcinoma (23).…”

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confidence: 99%

Receptor-interacting Protein Kinase 4 and Interferon Regulatory Factor 6 Function as a Signaling Axis to Regulate Keratinocyte Differentiation

Kwa

Huynh

et al. 2014

Journal of Biological Chemistry

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Background: RIPK4 and IRF6 are important for epidermal development. However, whether they function together to regulate keratinocyte differentiation has not been addressed. Results: RIPK4 directly activates IRF6, resulting in expression of the transcriptional regulators GRHL3 and OVOL1. Conclusion: RIPK4 and IRF6 promote keratinocyte differentiation by functioning as a signaling axis. Significance: This study reveals how mutations in RIPK4 may cause epidermal disorders.

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“…However, cases of patients who lived until childhood have been reported [2]. BPS is seen more often in Mediterranean countries, and it is seen that this form, which is deadly and hereditary transitive, is repeated for generations [1,2]. As in our case, due to reasons such as the continuation of lineage and ostracisation, deadly incidents and sick children are not revealed and marriages among relatives are realized.…”

mentioning

confidence: 71%

“…Various abnormalities are seen such as atypical face, hypoplastic nose, short palpebral fissures, microcephaly, syndactyly, popliteal webbing, genital abnormalities, and ectodermal anomalies. On performing ultrasound in the first trimester, limb abnormalities can be diagnosed and identified [1]. Visceral organs may be affected, but usually, they are reported to be normal and functioning.…”

mentioning

confidence: 99%