单纯型大疱性表皮松解症3家系遗传分析

doi:10.12372/jcp.2026.25e1603

临床儿科杂志 ›› 2026, Vol. 44 ›› Issue (5): 431-437.doi: 10.12372/jcp.2026.25e1603

单纯型大疱性表皮松解症3家系遗传分析

秦思佳¹^,²^,³^,^*, 崔梦醒⁴^,^*, 张悦⁵, 张贵源¹^,²^,³, 郎鹏翔¹^,²^,³, 陈刚¹^,²^,³(), 梁波¹^,²^,³()

1.安徽医科大学第一附属医院皮肤科（安徽合肥 230022）
2.安徽医科大学皮肤病学教育部重点实验室（安徽合肥 230022）
3.炎症免疫性疾病安徽省实验室（安徽合肥 230022）
4.北京大学人民医院检验科（北京 100044）
5.安徽医科大学第一附属医院检验科（安徽合肥 230022）

收稿日期:2025-12-16 录用日期:2026-04-13 出版日期:2026-05-15 发布日期:2026-05-08
通讯作者: 梁波，电子信箱：liangbo@fy.ahmu.edu.cn; 陈刚，电子信箱：gangchen@ahmu.edu.cn
作者简介:*具有同等贡献
作者贡献（Authors’ Contributions）
秦思佳负责实验与论文初稿撰写，郎鹏翔提出研究思路，设计研究方案，张悦、张贵源负责临床资料的收集与整理，崔梦醒负责数据整理与分析，梁波负责课题设计与样本采集，陈刚负责数据核对与论文修改。
基金资助:
安徽省自然科学基金面上项目(2308085MH263);安徽省高校科研重大项目(2024AH040109);2023年度安徽省新时代育人省级质量工程项目（研究生教育）(2023zyxwjxalk051)

A genetic study of three families with epidermolysis bullosa simplex

QIN Sijia¹^,²^,³^,^*, CUI Mengxing⁴^,^*, ZHANG Yue⁵, ZHANG Guiyuan¹^,²^,³, LANG Pengxiang¹^,²^,³, CHEN Gang¹^,²^,³(), LIANG Bo¹^,²^,³()

1. Department of Dermatology,the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China
2. Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei 230022, Anhui, China
3. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei 230022, Anhui, China
4. Department of Clinical Laboratory, Peking University People's Hospital, Beijing 100044, China
5. Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China

Received:2025-12-16 Accepted:2026-04-13 Published:2026-05-15 Online:2026-05-08

摘要/Abstract

摘要：

目的分析3个单纯型大疱性表皮松解症（EBS）家系的致病基因变异特征，探讨基因型与表型的关联性，为EBS的分子诊断和遗传咨询提供依据。方法收集2019年至2023 年就诊的3个EBS家系为研究对象，行全外显子组测序筛选候选致病突变，经Sanger测序验证；利用AlphaFold 3及PDBePISA对KRT5新突变进行蛋白结构建模与功能预测；制定个体化干预方案并随访。结果 3个家系患者均符合EBS局限型（EBS-loc）诊断标准，且在皮损范围、严重程度及病程演变上存在差异。遗传学检测发现家系1携带KRT5基因新错义突变 (NM_000424.4)：c.1291A>G（p.Lys431Glu），为常染色体显性遗传；家系2携带KRT14基因已知错义突变（NM_000526.5）：c.374G>A（p.Arg125His），与表型共分离；家系3携带KRT5基因新发错义突变（NM_000424.4）：c.428T>A（p.Val143Asp）。蛋白结构预测显示 p.Lys431Glu 突变会削弱KRT5-KRT14异源二聚体的结合亲和力与结构稳定性。结论本研究发现KRT5（NM_000424.4）：c.1291A>G（p.Lys431Glu）为未报道新突变，丰富了EBS突变谱，蛋白结构预测揭示了该突变致病机制。个体化综合管理可显著改善EBS患者预后，基因检测对明确诊断、遗传咨询及个体化管理提供了重要依据。

关键词: 大疱性表皮松解症, KRT5基因, KRT14基因, 基因变异

Abstract:

Objective To analyze the pathogenic gene mutation characteristics in three families with epidermolysis bullosa simplex (EBS) and explore the association between genotype and phenotype, providing evidence for molecular diagnosis and genetic counseling of EBS. Methods Three EBS families admitted between 2019 and 2023 were enrolled. Whole-exome sequencing (WES) was performed to screen candidate pathogenic mutations, followed by Sanger sequencing validation. For the novel KRT5 mutation, protein structure modeling and functional prediction were conducted using AlphaFold 3 and PDBePISA. Individualized intervention plans were formulated and followed up. Results All patients in the three families met the diagnostic criteria for localized EBS (EBS-loc), and there were differences in the extent, severity, and disease course. Genetic testing revealed that family 1 carried a novel missense mutation in the KRT5 gene (NM_000424.4): c.1291A>G (p.Lys431Glu), which was an autosomal dominant inheritance; family 2 carried a known missense mutation in the KRT14 gene (NM_000526.5): c.374G>A (p.Arg125His), which was co-segregated with the phenotype; family 3 carried a novel missense mutation in the KRT5 gene (NM_000424.4): c.428T>A (p.Val143Asp). Protein structure prediction showed that the p.Lys431Glu mutation would weaken the binding affinity and structural stability of the KRT5-KRT14 heterodimer. Conclusion This study identified a novel KRT5 (NM_000424.4): c.1291A>G (p.Lys431Glu) mutation that has not been reported before, enriching the EBS mutation spectrum. Protein structure prediction revealed the pathogenic mechanism of this mutation. Individualized comprehensive management can significantly improve the prognosis of EBS patients, and genetic testing provides an important basis for clear diagnosis, genetic counseling, and individualized management.

Key words: epidermolysis bullosa, KRT5, KRT14, gene mutation

中图分类号:

秦思佳, 崔梦醒, 张悦, 张贵源, 郎鹏翔, 陈刚, 梁波. 单纯型大疱性表皮松解症3家系遗传分析[J]. 临床儿科杂志, 2026, 44(5): 431-437.

QIN Sijia, CUI Mengxing, ZHANG Yue, ZHANG Guiyuan, LANG Pengxiang, CHEN Gang, LIANG Bo. A genetic study of three families with epidermolysis bullosa simplex[J]. Journal of Clinical Pediatrics, 2026, 44(5): 431-437.

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参考文献 18

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家系	患者	编号	性别	年龄	发病年龄	变异基因	突变位置	突变情况	氨基酸改变	现皮损情况
1	P1	Ⅲ-1	男	5岁	1岁	KRT5	exon7	（NM_000424.4）：c.1291A>G	p.Lys431Glu	足底和趾间多发水疱，部分伴破溃、结痂
1	P2	II-1	男	28岁	1岁	KRT5	exon7	（NM_000424.4）：c.1291A>G	p.Lys431Glu	足底角化过度、角质层增厚
2	P3	II-3	男	30岁	3天	KRT14	exon1	（NM_000526.5）：c.374G>A	p.Arg125His	腰部、腿部可见褐色色素沉着
2	P4	Ⅲ-3	男	5月	12天	KRT14	exon1	（NM_000526.5）：c.374G>A	p.Arg125His	下颌部、腰部、手掌、足底部散在分布硬币大小水疱
3	P5	Ⅲ-1	女	5月	刚出生时	KRT5	exon1	（NM_000424.4）：c.428T>A	p.Val143Asp	足部可见水疱，破溃后形成结痂

指标	野生型二聚体	突变型二聚体（p.Lys431Glu）	变化趋势
结合自由能(ΔG of binding)	-197.1	-178.9	降低
界面面积（interface area）	9 685.6	8 139.4	减少
氢键数量（hydrogen bonds）	56	37	减少
盐桥数量（salt bridges）	26	21	减少

单纯型大疱性表皮松解症3家系遗传分析

A genetic study of three families with epidermolysis bullosa simplex

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