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

Area of Science:

• Genetics
• Dermatology
• Biochemistry

Background:

• Nagashima-type palmoplantar keratoderma (NPPK) is a rare genetic skin disorder.
• It predominantly affects East Asian populations and is linked to SERPINB7 gene variants.
• The functional consequences of some SERPINB7 variants are not fully understood.

Purpose of the Study:

• To investigate the genetic basis of NPPK in Chinese patients.
• To identify and characterize pathogenic variants in the SERPINB7 gene.
• To elucidate the functional impact of identified SERPINB7 variants on protein function and disease mechanism.

Main Methods:

• Sanger sequencing was used to identify SERPINB7 variants in three unrelated Chinese NPPK patients.
• Transcript analysis was performed to assess mRNA splicing.
• Protein structural modeling and legumain protease activity assays were conducted to evaluate protein function.

Main Results:

• Biallelic pathogenic SERPINB7 variants were identified in all patients.
• A novel in-frame indel variant (c.806_814delinsT) and three known founder variants were detected.
• The c.455G>T variant acted as a missense variant (p.Gly152Val) without affecting splicing.
• Both novel and known variants impaired SERPINB7's inhibitory function, increasing legumain activity.

Conclusions:

• The study expands the known spectrum of SERPINB7 mutations associated with NPPK.
• Novel insights into the pathogenicity of specific SERPINB7 variants (c.806_814delinsT and c.455G>T) in the Chinese population were provided.
• Dysfunctional SERPINB7 leading to elevated legumain activity is a key mechanism in these NPPK cases.