MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK; Institute of Child Health, University College London, London WC1N 1EH, UK.
MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK; Institute of Child Health, University College London, London WC1N 1EH, UK; Inherited Metabolic Diseases Unit, Great Ormond Street Hospital, London WC1N 3JH, UK.
Biochim Biophys Acta Mol Basis Dis. 2018 May;1864(5 Pt A):1609-1621. doi: 10.1016/j.bbadis.2018.01.028. Epub 2018 Jan 31.
Mutations in VPS33B and VIPAS39 cause the severe multisystem disorder Arthrogryposis, Renal dysfunction and Cholestasis (ARC) syndrome. Amongst other symptoms, patients with ARC syndrome suffer from severe ichthyosis. Roles for VPS33B and VIPAR have been reported in lysosome-related organelle biogenesis, integrin recycling, collagen homeostasis and maintenance of cell polarity. Mouse knockouts of Vps33b or Vipas39 are good models of ARC syndrome and develop an ichthyotic phenotype. We demonstrate that the skin manifestations in Vps33b and Vipar deficient mice are histologically similar to those of patients with ARC syndrome. Histological, immunofluorescent and electron microscopic analysis of Vps33b and Vipar deficient mouse skin biopsies and isolated primary cells showed that epidermal lamellar bodies, which are essential for skin barrier function, had abnormal morphology and the localisation of lamellar body cargo was disrupted. Stratum corneum formation was affected, with increased corneocyte thickness, decreased thickness of the cornified envelope and reduced deposition of lipids. These defects impact epidermal homeostasis and lead to abnormal barrier formation causing the skin phenotype in Vps33b and Vipar deficient mice and patients with ARC syndrome.
VPS33B 和 VIPAS39 的突变会导致严重的多系统障碍性疾病——关节挛缩、肾功能障碍和胆汁淤积（ARC）综合征。除其他症状外，ARC 综合征患者还患有严重的鱼鳞癣。VPS33B 和 VIPAR 在溶酶体相关细胞器生物发生、整合素循环、胶原蛋白动态平衡和细胞极性维持中发挥作用。Vps33b 或 Vipas39 的小鼠敲除是 ARC 综合征的良好模型，并出现鱼鳞癣表型。我们证明，Vps33b 和 Vipar 缺陷型小鼠的皮肤表现与 ARC 综合征患者的皮肤表现在组织学上相似。对 Vps33b 和 Vipar 缺陷型小鼠皮肤活检和分离的原代细胞进行组织学、免疫荧光和电子显微镜分析表明，表皮板层小体对皮肤屏障功能至关重要，其形态异常，板层体货物的定位被打乱。角质层形成受到影响，角朊细胞厚度增加，角化包膜厚度减小，脂质沉积减少。这些缺陷影响表皮动态平衡，导致异常的屏障形成，从而导致 Vps33b 和 Vipar 缺陷型小鼠以及 ARC 综合征患者的皮肤表型。
