Functional Characterization of a Novel In-Frame Indel and a Founder Variant in SERPINB7 Associated With Palmoplantar...

Nagashima-type palmoplantar keratoderma (NPPK) is a hereditary non-epidermolytic keratoderma predominantly reported in East Asian populations. It is mainly caused by biallelic loss-of-function variants in SERPINB7, but the functional impact of certain variants remains unclear. In this study, we performed Sanger sequencing on three unrelated Chinese patients with clinically diagnosed NPPK and identified biallelic pathogenic SERPINB7 variants in all cases. Among these, a novel in-frame indel variant (c.806_814delinsT, p.Ser269_Glu273delinsLeu) and three known founder variants (c.796C>T, c.522dupT, and c.455G>T) were detected. Transcript analysis revealed that the c.455G>T variant, despite being located at the exon-intron 6 junction, functions as a missense variant (p.Gly152Val) without affecting mRNA splicing. Functional studies, including protein structural modeling and legumain protease activity assays, revealed that both variants impaired the inhibitory function of SERPINB7, leading to increased legumain activity. These findings expand the mutational spectrum of SERPINB7 and provide new insights into the pathogenicity of the c.806_814delinsT and c.455G>T variants in the Chinese population.