A sporadic case of Nagashima-type palmoplantar keratosis caused by gene mutation in <i>SERPINB7</i>

Cx, Li; Sq, Zhang; Wen, Jie; Pj, Chen; Qx, Liu; Han, Koeun; Zeng, Kang; Xb, Zhang

doi:10.1111/ced.12849

Cited by 4 publications

(4 citation statements)

References 5 publications

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“…In addition, fungal infections and palmoplantar skin peeling were reported, but especially palmoplantar skin peeling may be underdiagnosed as the data were lacking for the majority. Skin histology in SERPINA12 patients shows acanthosis with hypergranulosis and keratohyalin granules, and hyperkeratosis, compatible with histological findings with SERPINB7 variants 2,4,10,12–16 . Similar to SERPINA12 patients, most SERPINB7 patients were Asian.…”

Section: Discussionsupporting

confidence: 60%

“…Skin histology in SERPINA12 patients shows acanthosis with hypergranulosis and keratohyalin granules, and hyperkeratosis, compatible with histological findings with SERPINB7 variants. 2,4,10,[12][13][14][15][16] Similar to SERPINA12 patients, most SER-PINB7 patients were Asian. Interestingly, both the SERPI-NA12-and SERPINB7-related hPPK are indicated enriched in Asian and Finnish populations by founder effects.…”

Section: Discussionmentioning

confidence: 90%

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A novel SERPINA12 variant and first European patients with diffuse palmoplantar keratoderma

Brandt,

Harjama,

Elomaa

et al. 2023

Acad Dermatol Venereol

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BackgroundHereditary palmoplantar keratodermas (hPPKs) comprise a heterogeneous group of skin disorders characterized by persistent palmoplantar hyperkeratosis. Loss‐of‐function variants in a serine peptidase inhibitor, SERPINA12, have recently been implicated in autosomal recessive diffuse hPPK. The disorder appears to share similarities with another hPPK associated with protease overactivity, namely Nagashima‐type PPK (NPPK) caused by biallelic variants in SERPINB7.ObjectivesThe aim of this study was to enhance the understanding of the clinical and genetic characteristics of serine protease‐related hPPKs caused by variants in SERPINA12 and SERPINB7.MethodsWhole‐exome sequencing (WES) was performed for hPPK patients. Haplotype analysis was completed for the patients with identified recessive SERPINA12 variants and their available family members. In addition, the current literature of SERPINA12‐ and SERPINB7‐related hPPKs was summarized.ResultsThe phenotype of SERPINA12‐related hPPK was confirmed by reporting three new SERPINA12 patients, the first of European origin. A novel SERPINA12 c.1100G>A p.(Gly367Glu) missense variant was identified confirming that the variant spectrum of SERPINA12 include both truncating and missense variants. The previously reported SERPINA12 c.631C>T p.(Arg211*) was indicated enriched in the Finnish population due to a plausible founder effect. In addition, SERPINA12 hPPK patients were shown to share a similar phenotype to patients with recessive variants in SERPINB7. The shared phenotype included diffuse transgradient PPK since birth or early childhood and frequent palmoplantar hyperhidrosis, aquagenic whitening and additional hyperkeratotic lesions in non‐palmoplantar areas. SERPINA12 and SERPINB7 hPPK patients cannot be distinguished without genetic analysis.ConclusionsRecessive variants in SERPINA12 and SERPINB7 leading to protease overactivity and hPPK produce a similar phenotype, indistinguishable without genetic analysis. SERPINA12 variants should be assessed also in non‐Asian patients with diffuse transgradient PPK. Understanding the role of serine protease inhibitors will provide insights into the complex proteolytic network in epidermal homeostasis.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 90%

A novel SERPINA12 variant and first European patients with diffuse palmoplantar keratoderma

Brandt,

Harjama,

Elomaa

et al. 2023

Acad Dermatol Venereol

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“…We hypothesized that NPPK represents an ideal readthrough target because >90% of the reported patients carry the TGAA nonsense mutation c.796C>T (Hashimoto et al, 2017;Hida et al, 2015;Kubo et al, 2013;Li et al, 2016;Miyauchi et al, 2016;Mizuno et al, 2014;Nakajima et al, 2017;On et al, 2017;Shiohama et al, 2016;Suzuki et al, 2015;Yin et al, 2014;Zhang et al, 2016), and the mutant mRNA is likely to escape NMD, as it occurs in the last exon of the gene. The estimated number of NPPK patients carrying c.796C>T is extremely large-at least 0.15 million in Japan and China-because the allele frequency of this mutation is >0.01 in the Japanese and Chinese populations (Kubo et al, 2013), which again makes the mutation a very attractive therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

Gentamicin-Induced Readthrough and Nonsense-Mediated mRNA Decay of SERPINB7 Nonsense Mutant Transcripts

Ohguchi

Nomura

Suzuki

et al. 2018

Journal of Investigative Dermatology

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Nagashima-type palmoplantar keratosis (NPPK) is an autosomal recessive skin disorder with a high, unmet medical need that is caused by mutations in SERPINB7. Almost all NPPK patients carry the founder nonsense mutation c.796C>T (p.Arg266Ter) in the last exon of SERPINB7. Here we sought to determine whether topical nonsense-suppression (readthrough) therapy using gentamicin is applicable to NPPK. First, we demonstrated that gentamicin enhanced readthrough activity in cells transfected with SERPINB7 cDNA carrying the mutation and promoted full-length SERPINB7 protein synthesis in NPPK keratinocytes. We next conducted an investigator-blinded, randomized, bilaterally controlled compassionate use study of topical gentamicin in which five NPPK patients with c.796C>T were enrolled. Patients' self-reported improvement of hyperkeratosis was significantly greater on the gentamicin side than the control side (P = 0.0349). In two patients, hyperkeratosis was improved on the gentamicin side, as determined by a blinded-investigator assessment. These results indicate the therapeutic potential of topical gentamicin for NPPK. Unexpectedly, we also found that mutant SERPINB7 mRNAs harboring r.796c>u were degraded by nonsense-mediated mRNA decay. Furthermore, the truncated SERPINB7 protein was degraded via a proteasome-mediated pathway. These findings provide important insights into the mRNA/protein quality-control system in humans, which could be a potential therapeutic target for genetic diseases.

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“…We reviewed 32 NPPK relevant studies since 2013, totaling 389 cases (Table S1). 1–5,17,19–43 Twenty‐nine pathogenic mutations in SERPINB7 were summarized. Only eight out of 389 NPPK cases with a single heterozygous mutation were identified as patients due to either clear family history or undetermined second mutation.…”

Section: Discussionmentioning

confidence: 99%

SERPINB7 mutation causes Nagashima‐type palmoplantar keratosis and its spatiotemporal expression in zebrafish

Lyu

Zhang

Liu

et al. 2023

Experimental Dermatology

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Nagashima-type palmoplantar keratosis (NPPK) is an autosomal recessive disorder with the main clinical manifestations of erythema, scales and keratotic plaques. In 2013, Kubo et al. 1 identified the causative gene as SERPINB7 by whole-exome sequencing (WES) in three unrelated Japanese NPPK patients. Currently, NPPK cases are mainly reported in Asian populations. Domestic and foreign studies have confirmed the founder effect of the c.796C>T mutation in NPPK. [2][3][4][5] The prevalence of NPPK based on large samples is estimated as 0.975/10 000 in the Chinese population. 6 SERPINB7 encodes the serine protease inhibitor subfamily B member 7 isoform, expressed explicitly in cells of the stratum corneum and stratum granulosum. 1,7 Although the causative gene of

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A sporadic case of Nagashima-type palmoplantar keratosis caused by gene mutation in SERPINB7

Cited by 4 publications

References 5 publications

A novel SERPINA12 variant and first European patients with diffuse palmoplantar keratoderma

A novel SERPINA12 variant and first European patients with diffuse palmoplantar keratoderma

Gentamicin-Induced Readthrough and Nonsense-Mediated mRNA Decay of SERPINB7 Nonsense Mutant Transcripts

SERPINB7 mutation causes Nagashima‐type palmoplantar keratosis and its spatiotemporal expression in zebrafish

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