Abstract：
SERPINA11 is a hitherto poorly characterised gene belonging to Clade A of the SERPIN superfamily, with unknown expression pattern and functional significance. We report a perinatal lethal phenotype in two foetuses from the same family associated with a biallelic loss of function variant in SERPINA11, and provide functional evidence to support its candidature as a Mendelian disorder. The SERPINA11 variant-associated foetal phenotype is characterised by gross and histopathological features of extracellular matrix disruption. Western blot and immunofluorescence analyses revealed SERPINA11 expression in multiple mouse tissues, with pronounced expression in the bronchiolar epithelium. We observed a significant decrease in SERPINA11 immunofluorescence in the affected foetal lung compared with a healthy gestation-matched foetus. Protein expression data from HEK293T cell lines following site-directed mutagenesis support the loss of function nature of the variant. Transcriptome analysis from the affected foetal liver indicated the possibility of reduced SERPINA11 transcript abundance. This novel serpinopathy appears to be a consequence of the loss of inhibition of serine proteases involved in extracellular matrix remodelling, revealing SERPINA11 as a protease inhibitor critical for embryonic development.
摘要：
SERPINA11是迄今为止表征不佳的基因，属于SERPIN超家族的A分支，具有未知的表达模式和功能意义。我们报告了来自同一家族的两个胎儿的围产期致死表型，该表型与SERPINA11中的双等位基因功能丧失有关，并提供了功能证据以支持其候选为孟德尔病。SERPINA11变体相关胎儿表型的特征在于细胞外基质破坏的总体和组织病理学特征。蛋白质印迹和免疫荧光分析显示SERPINA11在多个小鼠组织中表达，在细支气管上皮中明显表达。与健康的妊娠匹配胎儿相比，我们观察到受影响胎儿肺中SERPINA11免疫荧光的显着降低。定点诱变后来自HEK293T细胞系的蛋白质表达数据支持变体的功能性质的丧失。受累胎儿肝脏的转录组分析表明SERPINA11转录物丰度降低的可能性。这种新的血清病似乎是细胞外基质重塑中涉及的丝氨酸蛋白酶抑制丧失的结果。显示SERPINA11是对胚胎发育至关重要的蛋白酶抑制剂。
