背景:遗传性掌底角化病(hPPKs)包括一组以持续的掌底角化过度为特征的异质性皮肤病。丝氨酸肽酶抑制剂中的功能丧失变体,SERPINA12最近与常染色体隐性遗传弥漫性hPPK有关。该疾病似乎与另一种与蛋白酶过度活性相关的hPPK有相似之处,即由SERPINB7双等位基因变异体引起的长岛型PPK(NPPK)。
目的:本研究的目的是增强对由SERPINA12和SERPINB7变异体引起的丝氨酸蛋白酶相关hPPK的临床和遗传特征的理解。
方法:对hPPK患者进行全外显子组测序(WES)。对具有鉴定的隐性SERPINA12变异体及其可用家庭成员的患者完成单倍型分析。此外,总结了SERPINA12-和SERPINB7相关hPPKs的当前文献。
结果:通过报告三名新的SERPINA12患者,证实了SERPINA12相关hPPK的表型,第一个起源于欧洲。鉴定了一种新的SERPINA12c.1100G>Ap。(Gly367Glu)错义变体,证实了SERPINA12的变体谱包括截短和错义变体。先前报道的SERPINA12c.631C>Tp。(Arg211*)由于合理的创始人效应而在芬兰人口中富集。此外,SERPINA12hPPK患者与SERPINB7隐性变异患者具有相似的表型。共有表型包括自出生或儿童早期以来的弥漫性跨梯度PPK和频繁的掌plant多汗症,非掌足底区域的水生性美白和额外的角化过度病变。SERPINA12和SERPINB7hPPK患者在没有遗传分析的情况下无法区分。
结论:SERPINA12和SERPINB7的隐性变异导致蛋白酶过度活性和hPPK产生相似的表型,没有遗传分析就无法区分。SERPINA12变体也应在弥漫性跨梯度PPK的非亚洲患者中进行评估。了解丝氨酸蛋白酶抑制剂的作用将提供对表皮稳态中复杂蛋白水解网络的见解。
BACKGROUND: Hereditary 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.
OBJECTIVE: The 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.
METHODS: Whole-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.
RESULTS: The 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.
CONCLUSIONS: Recessive 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.