RARE DISEASE
Palmoplantar keratoderma, Nagashima type
Palmoplantar keratoderma, Nagashima type
Palmoplantar keratoderma, Nagashima type
Synonyms: PPK, Nagashima type, Palmoplantar hyperkeratosis, Nagashima type
Synonyms: PPK, Nagashima type, Palmoplantar hyperkeratosis, Nagashima type
Synonyms: PPK, Nagashima type, Palmoplantar hyperkeratosis, Nagashima type
Drug discovery
22
papers
On emerging therapies
Overview
Palmoplantar keratoderma, Nagashima type (PPKN) is an autosomal recessive disorder caused by biallelic mutations in SERPINB7, encoding a serine protease inhibitor. It manifests as diffuse, non-progressive palmoplantar hyperkeratosis with erythema extending to dorsal surfaces (transgrediens), hyperhidrosis, and foul odor. Histopathology reveals hyperkeratosis without epidermolysis, and characteristic white spongy lesions after water immersion. It is prevalent in East Asia and often misdiagnosed as mild mal de Meleda [1][5][9][15][17].
Burden
Chronic hyperhidrosis, odor, and maceration impair quality of life (e.g., Dermatology Life Quality Index scores) [3][15][18].
Associated with increased risk of dermatophyte infections and psychosocial stigma [9][15].
Non-progressive but lifelong condition with significant daily care requirements [1][5][17].
Therapies
Topical agents: Emollients (urea, salicylic acid), retinoids, and vitamin D analogs for hyperkeratosis [3][7][15].
Gentamicin ointment: Reduces hyperkeratosis and odor in nonsense mutation cases via readthrough therapy [3][7][11].
No curative treatments; management focuses on symptom relief and reducing infections (e.g., tinea pedis) [5][9][15].
Categories: rare genetic diseases, rare skin diseases
Research Papers
22 drug discovery papers about Palmoplantar keratoderma, Nagashima type, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
22 drug discovery papers about Palmoplantar keratoderma, Nagashima type, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-11 | Palmoplantar Keratoderma: A Mechanism-Based Disease Classification.
Palmoplantar keratoderma (PPK) represents a diagnostically challenging group of genodermatoses due to its extensive genetic heterogeneity. Although multiple causative genes have been identified, the clinical utility of these discoveries remains limited, because few studies directly compare how distinct molecular mechanisms translate into divergent clinical phenotypes. We describe and analyze three paradigmatic PPK cases with genetically confirmed diagnoses involving SERPINB7-related Nagashima-type PPK, TRPV3-related Olmsted spectrum disorder, and KRT1-associated PPK. Clinical features, disease severity, and genetic mutations were systematically compared. These observations generated a novel classification framework and were then integrated with a comprehensive review of contemporary literature to contextualize and support the comparative findings. Three patients with palmoplantar keratoderma (PPK) harboring distinct pathogenic variants were analyzed and comparatively evaluated. Despite overlapping clinical features, these cases corresponded to three distinct pathogenic mechanisms: defective barrier homeostasis, overactive signaling, and structural collapse. A mechanism-based classification framework was established accordingly. Through comprehensive literature review, 56 PPK-associated genes were identified, the majority of which could be systematically assigned to the three mechanistic categories based on their primary molecular functions. This study highlights that clinically overlapping PPK phenotypes arise from distinct molecular mechanisms. Our mechanism-based classification provides a framework linking genotype to pathogenesis, which may improve diagnostic precision, support the development of mechanism-targeted therapeutic strategies, and thereby advancing personalized management in hereditary PPK.
2026-06-29 | Molecular insights into nagashima-type palmoplantar keratoderma: SERPINB7 mutation spectrum and mechanistic perspectives.
Nagashima-type palmoplantar keratoderma (NPPK) is a common inherited palmoplantar keratoderma predominantly affecting East Asian populations and caused by biallelic loss-of-function variants in the SERPINB7 gene. Clinically, NPPK is characterized by diffuse, non-progressive hyperkeratoderma of the palms and soles with erythema extending beyond the palmoplantar margins, frequently accompanied by hyperhidrosis and malodor. Although the disease course is generally benign, these features may lead to a considerable psychosocial burden. Advances in next-generation sequencing have expanded the mutational spectrum of SERPINB7 and clarified founder effects in different populations, while mechanistic studies have highlighted the essential role of SERPINB7 in maintaining epidermal protease-antiprotease balance and barrier homeostasis. These insights have enabled the development of mutation-targeted therapeutic approaches, most notably topical gentamicin-induced readthrough therapy for nonsense mutations. This review summarizes current knowledge and recent advances in the epidemiology, genetics, pathogenesis, clinical features, and management of NPPK, with particular emphasis on emerging precision treatment strategies.
2026-04-26 | Identification of novel small molecule compounds with readthrough activity in Nagashima-type palmoplantar keratosis.
Nagashima-type palmoplantar keratosis (NPPK), the most common form of hereditary palmoplantar keratodermas in East Asian populations, is caused by biallelic loss-of-function mutations in SERPINB7 such as p.Arg266Ter (c.796 C>T). This mutation introduces a premature termination codon (PTC). Given the minimal efficacy of current drugs in improving NPPK skin phenotypes, we applied readthrough therapy to enable the production of functional proteins by allowing ribosomes to read through premature stop codons. To discover small molecule compounds with readthrough potency. Using high-throughput screening, we initially screened nearly 20,000 small molecule compounds. Using Western blot, we assessed the readthrough effectiveness of shortlisted compounds on the mutant SERPINB7 vector. We identified a promising compound and acquired structurally related compounds, comparing then their potency with that of gentamicin and ataluren. In addition, we evaluated the readthrough capability of the identified compounds on other 11 premature termination codons with different + 4 nucleotides. The identified hit compounds demonstrated superior readthrough efficacy than gentamicin and ataluren. Notably, our compounds were effective in enabling readthrough, particularly on UGAA and UAAG premature stop codons. Our research identified new compounds that effectively promote the readthrough of premature stop codons. In vitro, these compounds showed higher readthrough potency than drugs such as gentamicin or ataluren. These results suggest that these compounds could be promising therapeutic agents for genetic diseases caused by nonsense mutations.
2025-12-04 | Microbial dysbiosis and foot odor in Nagashima-type palmoplantar keratosis: Improvement with topical benzoyl peroxide.
Nagashima-type palmoplantar keratosis (also referred to as SERPINB7-related palmoplantar epidermal differentiation disorder) is the most common form of palmoplantar keratoderma in East Asia. It is characterized by erythematous hyperkeratosis, palmoplantar hyperhidrosis, and a distinctive foot odor that significantly impairs QOL. In this study, we aimed to clarify the etiology of this odor by investigating the plantar microbiome and evaluating the therapeutic effects of topical benzoyl peroxide. Compared with healthy controls, individuals with Nagashima-type palmoplantar keratosis exhibited significantly higher objective odor scores; increased bacterial load, especially in the intertoe area; and reduced microbial diversity. Corynebacterium and Staphylococcus were the predominant dysbiotic flora species. The topical application of benzoyl peroxide significantly reduced foot odor and bacterial load; increased microbial diversity; and selectively decreased Corynebacterium abundance, particularly that of C tuberculostearicum. These changes correlate with the species-specific susceptibility of skin-resident bacteria to benzoyl peroxide. Our findings suggest that microbial dysbiosis, especially the overgrowth of Corynebacterium species, is central to the pathogenesis of foot odor in Nagashima-type palmoplantar keratosis. Topical benzoyl peroxide is a promising therapeutic intervention for mitigating dysbiosis and its associated foot odor. This study highlights the potential of microbiome-targeted therapies for symptom relief in inherited skin disorders such as Nagashima-type palmoplantar keratosis.
2024-12-12 | Phenotypic and genotypic analysis of SERPINA12-related autosomal recessive palmoplantar keratoderma in southwestern China.
Hereditary palmoplantar keratoderma (hPPK) comprises a clinical and heterogeneous group of skin disorders characterized by hyperkeratosis of the palms and soles. Variants of SERPINA12 have been implicated in autosomal recessive diffuse hPPK, which shares similarities with Nagashima-type PPK due to biallelic variants in SERPINB7. To date, seven SERPINA12 variants have been found in 11 patients with biallelic SERPINA12 variants worldwide. Herein, we described six new cases of hPPK caused by biallelic SERPINA12 variants from southwestern China. Our study showed commonly extensive distribution of skin lesions and various comorbidities in patients with SERPINA12-related hPPK. Moreover, we revealed the variant c.635-7A>G was a founder variant in patients with SERPINA12-related hPPK in southwestern China. Our work is helpful to improve the knowledge of clinical and genetic characteristics of SERPINA12-related hPPK.
antibodies
2025-10-13 | Dupilumab treatment for Chinese Nagashima-type palmoplantar keratoderma associated with atopic dermatitis: a case report.
Patients with Nagashima-type palmoplantar keratoderma (NPPK) experience progressive, painful hyperkeratosis and fissuring of palms and soles that limits daily activities Due to the incomplete understanding of its pathogenesis, there are currently no effective treatments for NPPK. We report a 26-year-old woman with lifelong, worsening palmoplantar keratoderma, nail dystrophy, and concomitant atopic dermatitis refractory to topical treatments. Next-generation sequencing revealed compound heterozygous mutations in SERPINB7 (c.796C>T, p.Arg266Ter) and filaggrin (FLG, c.3321delA, p.Gly1109GlufsTer13), while her asymptomatic parents and brother carried only single heterozygous variants, underscoring the digenic pathogenesis in our patient. After 42 weeks of dupilumab treatment, palmoplantar keratosis and nail changes had almost completely resolved, and the eruption resembled mild chronic eczema. Dupilumab therefore appears to be a safe and effective option for digenic NPPK complicated by atopic dermatitis and warrants further investigation in larger cohorts.
2023-06-09 | SERPINB7 mutation causes Nagashima-type palmoplantar keratosis and its spatiotemporal expression in zebrafish.
Serine protease inhibitor B7 (SERPINB7) mutations have been reported to cause Nagashima-type palmoplantar keratosis (NPPK), but their biological effects are largely unknown. We conducted whole-exome sequencing and identified a c.796C>T (p.Arg266Ter) mutation in SERPINB7 in a Chinese pedigree, which presented as an autosomal recessive inheritance pattern. We assessed the function of SERPINB7 in homozygous and heterozygous mutation carriers, and the results suggested that the single c.796C>T mutation may alter the subcellular localization of SERPINB7. One of the homozygous mutation patients (II-3) was treated with ixekizumab and showed moderate improvement in keratinization. In addition, we analysed the spatiotemporal expression of serpinb1l1 and serpinb1l3, the zebrafish homologue of human SERPINB7, which is expressed in larvae and adults. In larvae, both serpinb1l1 and serpinb1l3 were expressed in the digestive tract. Then, we performed RT-PCR on adult fins based on similarity to the site of NPPK expression in humans and found that the genes were expressed in five fins (pectoral, pelvic, dorsal, anal and caudal) of the zebrafish distal extremity. Taken together, our results demonstrated that the single c.796C>T (p.Arg266Ter) mutation may alter the location of SERPINB7-encoded protein in the skin, while zebrafish SERPINB7 homologue was expressed in adult fins. These findings will enable us to construct knock-out models to explore the pathogenesis of palmoplantar keratosis.
oligonucleotides
2025-06-28 | A deep intronic founder variant in the SERPINB7 gene causing aberrant splicing is a potential therapeutic target for Nagashima-type palmoplantar keratoderma.
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. To characterize a deep intronic SERPINB7 variant's pathogenicity, elucidate its splicing dysregulation, and evaluate antisense oligonucleotide (ASO) therapy. 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. 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. 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.
proteins
2026-09-04 | Integrated bioinformatics analysis reveals convergent molecular signatures associated with SERPINB7 and SERPINA12 deficiency.
Pathogenic variants in SERPINA12 have recently been identified in patients with palmoplantar keratoderma (PPK). Clinically, SERPINA12-associated PPK shares substantial overlap with Nagashima-type palmoplantar keratoderma (NPPK) caused by SERPINB7 deficiency, although inflammatory manifestations appear to be more prominent in SERPINA12-associated disease. The molecular basis underlying these similarities and differences remains unclear. Virtual knockout analyses of SERPINA12 and SERPINB7 were performed using the scTenifoldKnk framework. Functional enrichment analyses, including GO, KEGG, and GSEA, were conducted to characterize perturbed biological pathways. Correlation analyses were performed using extracellular matrix (ECM)- and inflammation-related gene signatures. In addition, SERPINA12 was overexpressed in TNF-α-stimulated HaCaT keratinocytes to evaluate its effects on inflammatory cytokine expression. Both SERPINA12 and SERPINB7 were associated with ECM-related biological processes and pathways, suggesting a potential shared role in extracellular matrix homeostasis. However, SERPINA12 deficiency preferentially perturbed immune- and inflammation-related pathways, including Toll-like receptor signaling, interleukin signaling, and leukocyte activation. Consistently, SERPINA12 overexpression significantly reduced TNF-α, IL-8, and IL-1β expression in TNF-α-stimulated HaCaT cells. SERPINA12 and SERPINB7 are associated with extracellular matrix-associated functions that may account for their similar keratoderma phenotypes. In contrast, SERPINA12 additionally may exerts anti-inflammatory effects, providing a potential molecular explanation for the enhanced inflammatory manifestations observed in SERPINA12-associated PPK.
small molecules
2026-09-11 | Palmoplantar Keratoderma: A Mechanism-Based Disease Classification.
Palmoplantar keratoderma (PPK) represents a diagnostically challenging group of genodermatoses due to its extensive genetic heterogeneity. Although multiple causative genes have been identified, the clinical utility of these discoveries remains limited, because few studies directly compare how distinct molecular mechanisms translate into divergent clinical phenotypes. We describe and analyze three paradigmatic PPK cases with genetically confirmed diagnoses involving SERPINB7-related Nagashima-type PPK, TRPV3-related Olmsted spectrum disorder, and KRT1-associated PPK. Clinical features, disease severity, and genetic mutations were systematically compared. These observations generated a novel classification framework and were then integrated with a comprehensive review of contemporary literature to contextualize and support the comparative findings. Three patients with palmoplantar keratoderma (PPK) harboring distinct pathogenic variants were analyzed and comparatively evaluated. Despite overlapping clinical features, these cases corresponded to three distinct pathogenic mechanisms: defective barrier homeostasis, overactive signaling, and structural collapse. A mechanism-based classification framework was established accordingly. Through comprehensive literature review, 56 PPK-associated genes were identified, the majority of which could be systematically assigned to the three mechanistic categories based on their primary molecular functions. This study highlights that clinically overlapping PPK phenotypes arise from distinct molecular mechanisms. Our mechanism-based classification provides a framework linking genotype to pathogenesis, which may improve diagnostic precision, support the development of mechanism-targeted therapeutic strategies, and thereby advancing personalized management in hereditary PPK.
2026-06-29 | Molecular insights into nagashima-type palmoplantar keratoderma: SERPINB7 mutation spectrum and mechanistic perspectives.
Nagashima-type palmoplantar keratoderma (NPPK) is a common inherited palmoplantar keratoderma predominantly affecting East Asian populations and caused by biallelic loss-of-function variants in the SERPINB7 gene. Clinically, NPPK is characterized by diffuse, non-progressive hyperkeratoderma of the palms and soles with erythema extending beyond the palmoplantar margins, frequently accompanied by hyperhidrosis and malodor. Although the disease course is generally benign, these features may lead to a considerable psychosocial burden. Advances in next-generation sequencing have expanded the mutational spectrum of SERPINB7 and clarified founder effects in different populations, while mechanistic studies have highlighted the essential role of SERPINB7 in maintaining epidermal protease-antiprotease balance and barrier homeostasis. These insights have enabled the development of mutation-targeted therapeutic approaches, most notably topical gentamicin-induced readthrough therapy for nonsense mutations. This review summarizes current knowledge and recent advances in the epidemiology, genetics, pathogenesis, clinical features, and management of NPPK, with particular emphasis on emerging precision treatment strategies.
2026-04-26 | Identification of novel small molecule compounds with readthrough activity in Nagashima-type palmoplantar keratosis.
Nagashima-type palmoplantar keratosis (NPPK), the most common form of hereditary palmoplantar keratodermas in East Asian populations, is caused by biallelic loss-of-function mutations in SERPINB7 such as p.Arg266Ter (c.796 C>T). This mutation introduces a premature termination codon (PTC). Given the minimal efficacy of current drugs in improving NPPK skin phenotypes, we applied readthrough therapy to enable the production of functional proteins by allowing ribosomes to read through premature stop codons. To discover small molecule compounds with readthrough potency. Using high-throughput screening, we initially screened nearly 20,000 small molecule compounds. Using Western blot, we assessed the readthrough effectiveness of shortlisted compounds on the mutant SERPINB7 vector. We identified a promising compound and acquired structurally related compounds, comparing then their potency with that of gentamicin and ataluren. In addition, we evaluated the readthrough capability of the identified compounds on other 11 premature termination codons with different + 4 nucleotides. The identified hit compounds demonstrated superior readthrough efficacy than gentamicin and ataluren. Notably, our compounds were effective in enabling readthrough, particularly on UGAA and UAAG premature stop codons. Our research identified new compounds that effectively promote the readthrough of premature stop codons. In vitro, these compounds showed higher readthrough potency than drugs such as gentamicin or ataluren. These results suggest that these compounds could be promising therapeutic agents for genetic diseases caused by nonsense mutations.
2025-12-04 | Microbial dysbiosis and foot odor in Nagashima-type palmoplantar keratosis: Improvement with topical benzoyl peroxide.
Nagashima-type palmoplantar keratosis (also referred to as SERPINB7-related palmoplantar epidermal differentiation disorder) is the most common form of palmoplantar keratoderma in East Asia. It is characterized by erythematous hyperkeratosis, palmoplantar hyperhidrosis, and a distinctive foot odor that significantly impairs QOL. In this study, we aimed to clarify the etiology of this odor by investigating the plantar microbiome and evaluating the therapeutic effects of topical benzoyl peroxide. Compared with healthy controls, individuals with Nagashima-type palmoplantar keratosis exhibited significantly higher objective odor scores; increased bacterial load, especially in the intertoe area; and reduced microbial diversity. Corynebacterium and Staphylococcus were the predominant dysbiotic flora species. The topical application of benzoyl peroxide significantly reduced foot odor and bacterial load; increased microbial diversity; and selectively decreased Corynebacterium abundance, particularly that of C tuberculostearicum. These changes correlate with the species-specific susceptibility of skin-resident bacteria to benzoyl peroxide. Our findings suggest that microbial dysbiosis, especially the overgrowth of Corynebacterium species, is central to the pathogenesis of foot odor in Nagashima-type palmoplantar keratosis. Topical benzoyl peroxide is a promising therapeutic intervention for mitigating dysbiosis and its associated foot odor. This study highlights the potential of microbiome-targeted therapies for symptom relief in inherited skin disorders such as Nagashima-type palmoplantar keratosis.
2024-12-12 | Phenotypic and genotypic analysis of SERPINA12-related autosomal recessive palmoplantar keratoderma in southwestern China.
Hereditary palmoplantar keratoderma (hPPK) comprises a clinical and heterogeneous group of skin disorders characterized by hyperkeratosis of the palms and soles. Variants of SERPINA12 have been implicated in autosomal recessive diffuse hPPK, which shares similarities with Nagashima-type PPK due to biallelic variants in SERPINB7. To date, seven SERPINA12 variants have been found in 11 patients with biallelic SERPINA12 variants worldwide. Herein, we described six new cases of hPPK caused by biallelic SERPINA12 variants from southwestern China. Our study showed commonly extensive distribution of skin lesions and various comorbidities in patients with SERPINA12-related hPPK. Moreover, we revealed the variant c.635-7A>G was a founder variant in patients with SERPINA12-related hPPK in southwestern China. Our work is helpful to improve the knowledge of clinical and genetic characteristics of SERPINA12-related hPPK.
antibodies
2025-10-13 | Dupilumab treatment for Chinese Nagashima-type palmoplantar keratoderma associated with atopic dermatitis: a case report.
Patients with Nagashima-type palmoplantar keratoderma (NPPK) experience progressive, painful hyperkeratosis and fissuring of palms and soles that limits daily activities Due to the incomplete understanding of its pathogenesis, there are currently no effective treatments for NPPK. We report a 26-year-old woman with lifelong, worsening palmoplantar keratoderma, nail dystrophy, and concomitant atopic dermatitis refractory to topical treatments. Next-generation sequencing revealed compound heterozygous mutations in SERPINB7 (c.796C>T, p.Arg266Ter) and filaggrin (FLG, c.3321delA, p.Gly1109GlufsTer13), while her asymptomatic parents and brother carried only single heterozygous variants, underscoring the digenic pathogenesis in our patient. After 42 weeks of dupilumab treatment, palmoplantar keratosis and nail changes had almost completely resolved, and the eruption resembled mild chronic eczema. Dupilumab therefore appears to be a safe and effective option for digenic NPPK complicated by atopic dermatitis and warrants further investigation in larger cohorts.
2023-06-09 | SERPINB7 mutation causes Nagashima-type palmoplantar keratosis and its spatiotemporal expression in zebrafish.
Serine protease inhibitor B7 (SERPINB7) mutations have been reported to cause Nagashima-type palmoplantar keratosis (NPPK), but their biological effects are largely unknown. We conducted whole-exome sequencing and identified a c.796C>T (p.Arg266Ter) mutation in SERPINB7 in a Chinese pedigree, which presented as an autosomal recessive inheritance pattern. We assessed the function of SERPINB7 in homozygous and heterozygous mutation carriers, and the results suggested that the single c.796C>T mutation may alter the subcellular localization of SERPINB7. One of the homozygous mutation patients (II-3) was treated with ixekizumab and showed moderate improvement in keratinization. In addition, we analysed the spatiotemporal expression of serpinb1l1 and serpinb1l3, the zebrafish homologue of human SERPINB7, which is expressed in larvae and adults. In larvae, both serpinb1l1 and serpinb1l3 were expressed in the digestive tract. Then, we performed RT-PCR on adult fins based on similarity to the site of NPPK expression in humans and found that the genes were expressed in five fins (pectoral, pelvic, dorsal, anal and caudal) of the zebrafish distal extremity. Taken together, our results demonstrated that the single c.796C>T (p.Arg266Ter) mutation may alter the location of SERPINB7-encoded protein in the skin, while zebrafish SERPINB7 homologue was expressed in adult fins. These findings will enable us to construct knock-out models to explore the pathogenesis of palmoplantar keratosis.
oligonucleotides
2025-06-28 | A deep intronic founder variant in the SERPINB7 gene causing aberrant splicing is a potential therapeutic target for Nagashima-type palmoplantar keratoderma.
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. To characterize a deep intronic SERPINB7 variant's pathogenicity, elucidate its splicing dysregulation, and evaluate antisense oligonucleotide (ASO) therapy. 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. 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. 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.
proteins
2026-09-04 | Integrated bioinformatics analysis reveals convergent molecular signatures associated with SERPINB7 and SERPINA12 deficiency.
Pathogenic variants in SERPINA12 have recently been identified in patients with palmoplantar keratoderma (PPK). Clinically, SERPINA12-associated PPK shares substantial overlap with Nagashima-type palmoplantar keratoderma (NPPK) caused by SERPINB7 deficiency, although inflammatory manifestations appear to be more prominent in SERPINA12-associated disease. The molecular basis underlying these similarities and differences remains unclear. Virtual knockout analyses of SERPINA12 and SERPINB7 were performed using the scTenifoldKnk framework. Functional enrichment analyses, including GO, KEGG, and GSEA, were conducted to characterize perturbed biological pathways. Correlation analyses were performed using extracellular matrix (ECM)- and inflammation-related gene signatures. In addition, SERPINA12 was overexpressed in TNF-α-stimulated HaCaT keratinocytes to evaluate its effects on inflammatory cytokine expression. Both SERPINA12 and SERPINB7 were associated with ECM-related biological processes and pathways, suggesting a potential shared role in extracellular matrix homeostasis. However, SERPINA12 deficiency preferentially perturbed immune- and inflammation-related pathways, including Toll-like receptor signaling, interleukin signaling, and leukocyte activation. Consistently, SERPINA12 overexpression significantly reduced TNF-α, IL-8, and IL-1β expression in TNF-α-stimulated HaCaT cells. SERPINA12 and SERPINB7 are associated with extracellular matrix-associated functions that may account for their similar keratoderma phenotypes. In contrast, SERPINA12 additionally may exerts anti-inflammatory effects, providing a potential molecular explanation for the enhanced inflammatory manifestations observed in SERPINA12-associated PPK.
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