RIPK4 – Ectodermal Dysplasia Syndrome

Receptor-interacting serine/threonine kinase 4 (RIPK4) is essential for epidermal proliferation, differentiation and cell–cell adhesion. Autosomal recessive variants in RIPK4 disrupt the p63–IRF6 regulatory loop and adhesive junctions, leading to ectodermal dysplasia syndrome, characterized by cutaneous syndactyly, palmoplantar hyperkeratosis and orofacial synechiae.

Inheritance is autosomal recessive, with three unrelated probands reported to date. Two siblings with novel biallelic missense RIPK4 variants presented with cutaneous syndactyly and palmoplantar hyperkeratosis (PMID:35220430), and a separate individual harbored homozygous c.488G>A (p.Gly163Asp) confirmed by exome sequencing and segregation analysis in a consanguineous family.

Segregation analysis showed cosegregation of disease with homozygosity for pathogenic RIPK4 alleles in affected siblings (2 affected relatives). Variant spectrum includes missense substitutions within the kinase domain (e.g., c.488G>A (p.Gly163Asp)) that impair catalytic activity and cell adhesion.

Functional studies demonstrate that loss of RIPK4 kinase activity abrogates phosphorylation of IRF6, reduces PVRL4/nectin-4 expression, and alters desmosome morphology in patient keratinocytes, mirroring defects in epithelial differentiation and adhesion (PMID:35220430; PMID:25246526). In murine Ripk4-null models, epidermal hypoplasia and junctional defects phenocopy human ectodermal dysplasia (PMID:22197489).

Key experiments including in vitro kinase assays, coimmunoprecipitation, reporter assays and rescue studies establish haploinsufficiency of RIPK4 as the pathogenic mechanism and support the clinical relevance of genetic findings.

References

• Human molecular genetics • 2022 • RIPK4 regulates cell–cell adhesion in epidermal development and homeostasis. PMID:35220430
• American journal of human genetics • 2012 • Mutations in RIPK4 cause the autosomal-recessive form of popliteal pterygium syndrome. PMID:22197489
• The Journal of biological chemistry • 2014 • Receptor-interacting protein kinase 4 and interferon regulatory factor 6 function as a signaling axis to regulate keratinocyte differentiation. PMID:25246526

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