A deep intronic founder variant in the SERPINB7 gene causing aberrant splicing is a potential therapeutic target for Nagashima-type palmoplantar keratoderma

Yuqi Chen; Zhiming Chen; Siyuan Li; Juan Liu; Yihe Liu; Qingyue Fu; Wenbo Bu; Shuya Sun; Tianxiao Li; Ruiyu Xiang; Zhongya Song; Ran Mo; Yong Yang

doi:10.1016/j.jdermsci.2025.05.004

A deep intronic founder variant in the SERPINB7 gene causing aberrant splicing is a potential therapeutic target for Nagashima-type palmoplantar keratoderma

J Dermatol Sci. 2025 May 23:S0923-1811(25)00084-2. doi: 10.1016/j.jdermsci.2025.05.004. Online ahead of print.

Authors

Yuqi Chen¹, Zhiming Chen¹, Siyuan Li², Juan Liu³, Yihe Liu¹, Qingyue Fu⁴, Wenbo Bu⁵, Shuya Sun¹, Tianxiao Li¹, Ruiyu Xiang¹, Zhongya Song¹, Ran Mo⁶, Yong Yang⁷

Affiliations

¹ Genetic Skin Disease Center, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China.
² Department of Dermatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
³ Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
⁴ Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
⁵ Department of Dermatologic Surgery, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.
⁶ Genetic Skin Disease Center, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China. Electronic address: rmo@pumcderm.cams.cn.
⁷ Genetic Skin Disease Center, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China. Electronic address: yyang@pumcderm.cams.cn.

PMID: 40579253
DOI: 10.1016/j.jdermsci.2025.05.004

Abstract

Background: Nagashima-type palmoplantar keratoderma (NPPK), caused by biallelic SERPINB7 loss-of-function variants, lacks effective treatments. Intriguingly, monoallelic exonic variants are observed in some patients with NPPK, suggesting additional genetic variants.

Objective: To characterize a deep intronic SERPINB7 variant's pathogenicity, elucidate its splicing dysregulation, and evaluate antisense oligonucleotide (ASO) therapy.

Methods: A customized next-generation sequencing panel was applied to six Chinese NPPK patients. Pathological changes were analyzed by H&E staining and immunofluorescence. RNA extracted from palmar skin was assessed for splicing alterations. Plasmids were generated to evaluate the expression and function of mutant SERPINB7 protein. Haplotype analysis was conducted to confirm the founder effect. RNA pull-down assays and mass spectrometry were used to identify the key splicing factor. Minigene constructs were developed to characterize the splicing process in vitro. Finally, an ASO was designed to target this variant.

Results: A deep intronic SERPINB7 variant was identified in six NPPK patients, leading to pseudo-exon inclusion and the production of a truncated, dysfunctional SERPINB7 protein. Haplotype analysis confirmed it as a Chinese founder variant. RNA pull-down assays revealed excessive SRSF9 binding to the abnormal transcript. In vitro, the ASO successfully corrected the aberrant splicing.

Conclusion: This study established the pathogenicity of a deep intronic founder variant in SERPINB7 driving NPPK via SRSF9-mediated splicing dysregulation, demonstrating ASO therapeutic potential. Findings provide mechanistic insights and a targeted approach for precision therapy development for NPPK.

Keywords: Nagashima-type palmoplantar keratoderma; SERPINB7; aberrant splicing; antisense oligonucleotide; deep intronic variant; genetic therapy.