SERPINA11 related novel Serpinopathy- a perinatal lethal disorder
SERPINA11 is a hitherto poorly characterised gene belonging to Clade A of the SERPIN superfamily. The exact functional significance and expression pattern of this gene remains unknown. Here we report a perinatal lethal phenotype associated with biallelic loss of function variants in SERPINA11, and characterised by gross and histopathological features of extracellular matrix disruption. We found SERPINA11 protein expression in multiple mouse tissues and human fetal lungs. Immunofluorescence of the affected fetal lung revealed markedly reduced expression of SERPINA11 protein compared with healthy, gestation matched human fetal lung. Protein expression data from HEK293T cell lines following site directed mutagenesis is also presented to support the loss of function nature of the variant. This novel serpinopathy appears to be a consequence of loss of inhibition of serine proteases involved in extracellular matrix remodelling, revealing SERPINA11 as a protease inhibitor critical for embryonic development. Overall design: We conducted RNA-seq from liver tissue of a 19 week old human fetus carrying a homozygous nonsense variant in SERPINA11 gene, to study any alterations in the SERPINA11 transcript levels.