The brittle hair syndrome Trichothiodystrophy (TTD) is characterized by variable clinical features, including photosensitivity, ichthyosis, growth retardation, microcephaly, intellectual disability, hypogonadism, and anaemia. TTD-associated mutations typically cause unstable mutant proteins involved in various steps of gene expression, severely reducing steady-state mutant protein levels. However, to date, no such link to instability of gene-expression factors for TTD-associated mutations in MPLKIP/TTDN1 has been established. Here, we present seven additional TTD individuals with MPLKIP mutations from five consanguineous families, with a newly identified MPLKIP variant in one family. By mass spectrometry-based interaction proteomics, we demonstrate that MPLKIP interacts with core splicing factors and the lariat debranching protein DBR1. MPLKIP-deficient primary fibroblasts have reduced steady-state DBR1 protein levels. Using Human Skin Equivalents (HSEs), we observed impaired keratinocyte differentiation associated with compromised splicing and eventually, an imbalanced proteome affecting skin development and, interestingly, also the immune system. Our data show that MPLKIP, through its DBR1 stabilizing role, is implicated in mRNA splicing, which is of particular importance in highly differentiated tissue.

中文翻译：

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毛发硫营养不良相关的 MPLKIP 维持 DBR1 水平，以实现套索的适当脱支和外胚层分化

脆发综合征毛发硫营养不良 (TTD) 的临床特征多种多样，包括光敏性、鱼鳞病、生长迟缓、小头畸形、智力障碍、性腺功能减退和贫血。TTD 相关突变通常会导致参与基因表达各个步骤的不稳定突变蛋白，严重降低稳态突变蛋白水平。然而，迄今为止，尚未确定MPLKIP / TTDN1中 TTD 相关突变的基因表达因子的不稳定性与这种联系。在这里，我们介绍了来自 5 个近亲家庭的另外 7 名带有MPLKIP突变的 TTD 个体，其中一个家族中有一种新发现的MPLKIP变异。通过基于质谱的相互作用蛋白质组学，我们证明 MPLKIP 与核心剪接因子和套索脱支蛋白 DBR1 相互作用。MPLKIP缺陷的原代成纤维细胞的稳态 DBR1 蛋白水平降低。使用人类皮肤等效物 (HSE)，我们观察到与剪接受损相关的角质形成细胞分化受损，最终导致蛋白质组不平衡影响皮肤发育，有趣的是，还影响免疫系统。我们的数据表明，MPLKIP 通过其 DBR1 稳定作用，参与 mRNA 剪接，这在高度分化的组织中尤其重要。