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Researchers identified a genetic variant (c.905+1 G>T) in the SERPINA12 gene through whole exome sequencing of a Tunisian family affected by psoriasis vulgaris. This splice site mutation segregates with the disease in the family and computational analyses suggest it destabilizes the vaspin protein, impairing its ability to inhibit kallikrein 7 protease and reducing its anti-inflammatory function. The findings propose a novel disease mechanism linking psoriasis to metabolic disorders through the vaspin-kallikrein 7 pathway.
Why it matters
This discovery provides potential insights into why psoriasis patients often develop type 2 diabetes and other metabolic conditions. The identified genetic mechanism could inform development of targeted therapies for both psoriasis and its metabolic comorbidities, advancing precision medicine approaches for affected individuals.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Background Psoriasis vulgaris (PV) is an inflammatory skin disorder whose genetic basis has been widely explored through genome-wide association studies and biomarker analyses in heterogeneous cohorts. We adopted a family-based strategy focusing on nuclear families. Objective To identify genetic variants associated with PV and elucidate their impact on disease pathogenesis and metabolic comorbidities. Methods Whole exome sequencing (WES) was performed on a PV affected nuclear family. Integrative computational analyses; including structural modeling and molecular dynamics simulations were used to evaluate the impact of identified variants on protein stability and function. Potential links to inflammation and metabolic dysfunction were explored through literature-based interpretation. Results We identified a heterozygous splice site variant c.905+1 G>T in the SERPINA12 gene that segregates with PV in the studied family. Structural modeling and molecular dynamics revealed destabilization of the C-terminal region; impairing its serine protease inhibitory function. This alteration reduces vaspin is anti-inflammatory activity via kallikrein 7 (KLK7) inhibition. Conclusion This integrative WES-based approach identifies a PV associated mutation and suggests a new pathogenic mechanism involving the vaspin KLK7 axis. These findings offer insight into the link between PV and type 2 diabetes mellitus and highlight potential targets for precision medicine in psoriasis and associated metabolic disorders.
Source: SERPINA12 Splice Site Variant in Tunisian Familial Psoriasis Vulgaris: Segregation to Inheritance