MPLKIP deficient Human Skin Equivalents

ProblemTrichothiodystrophy (TTD) is a clinically and genetically heterogenous disorder characterized by a distinctive brittle hair phenotype, various ectodermal health issues, developmental and neurologic deficiencies. Despite its identification almost two decades ago, the exact function of one of the TTD-causative genes, MPLKIP/TTDN1, associated with a significant number of TTD cases, remains unclear.ResultsIn this study, we discovered that MPLKIP interacts with core splicing factors and plays a crucial role in maintaining DBR1 protein levels, which is severely reduced in MPLKIP-deficient cells. Using a reconstituted human 3D skin model, we demonstrate that MPLKIP deficiency disrupts gene expression, including abnormal pre-mRNA splicing and altered protein expression. MPLKIP deficiency impairs keratinocyte differentiation, resulting in leaky skin development and altered immune response.ImpactThis study uncovers a biological role of the enigmatic MPLKIP/TTDN1 protein and emphasizes the significant impact of MPLKIP deficiency on epithelial differentiation, tissue homeostasis and immunological skin barrier function, which are commonly affected in TTD. Notably, with the observed down regulation of immune related pathways in MPLKIP-deficient epithelia, future studies may provide potential targets for diagnostic and therapeutic interventions, particularly for addressing recurrent life-threatening infections associated with TTD.