Dermatology Hospital, Southern Medical University, Guangzhou, China.
Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses and National Clinical Research Center for Skin and Immune Diseases, Beijing, China.
J Eur Acad Dermatol Venereol. 2022 Oct;36(10):1857-1862. doi: 10.1111/jdv.18189. Epub 2022 May 12.
Epidermolytic palmoplantar keratoderma (EPPK) is characterized by diffuse hyperkeratosis affecting palms and soles with suprabasal epidermolysis or vacuolar degeneration histopathologically. The disorder is caused by heterozygous mutations in KRT9 or KRT1. Dominant-negative mutations in KRT1 could also result in epidermolytic ichthyosis with EPPK, a more severe entity affecting the entire body.
To investigate the genetic basis and pathogenesis of two unrelated patients with EPPK and knuckle pads, both of whom were born to consanguineous parents of Chinese origin.
Next-generation sequencing was applied to the two patients using genomic DNA extracted from peripheral blood. Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR), immunofluorescence (IF) staining and Western blot (WB) were employed to evaluate mRNA and protein expression level. Ultrastructural changes of skin lesion were analysed using transmission electron microscopy.
Two novel homozygous mutations, c.457C>T (p.Gln153*) and c.33C>G (p.Tyr11*) in KRT1, were identified in patients 1 and 2 respectively. The nonsense mutations were predicted to result in nonsense-mediated mRNA decay and absence of keratin 1, which was confirmed in the skin lesions from patient 1. Upregulated keratin 2 was detected both in the affected and unaffected skin samples from patient 1, while the protein abundance and distribution pattern of keratin 10 remained unchanged. An aberrant and clumped staining pattern of keratin 9 was noted in the palmar skin of patient 1.
Homozygous 'knockout' mutations in KRT1 resulted in EPPK with knuckle pads rather than epidermolytic ichthyosis. We speculated that sparing of non-acral skin might be due to compensatory effect of keratin 2 upregulation by forming heterodimer with keratin 10.
表皮松解性掌跖角化症（EPPK）的特征是弥漫性角化过度，影响手掌和足底，组织病理学表现为超基底层表皮松解或空泡变性。该疾病是由 KRT9 或 KRT1 的杂合突变引起的。KRT1 的显性负突变也可能导致表皮松解性鱼鳞病伴 EPPK，这是一种更严重的全身性疾病。
研究 2 例 EPPK 和指节垫的非相关患者的遗传基础和发病机制，这 2 例患者均出生于有血缘关系的中国裔父母。
使用外周血提取的基因组 DNA 对这 2 例患者进行下一代测序。采用定量逆转录聚合酶链反应（qRT-PCR）、免疫荧光（IF）染色和 Western blot（WB）检测评估 mRNA 和蛋白表达水平。采用透射电子显微镜分析皮肤病变的超微结构变化。
患者 1 和 2 分别发现 KRT1 中的 2 个新的纯合突变，c.457C>T（p.Gln153*）和 c.33C>G（p.Tyr11*）。无义突变预计会导致无义介导的 mRNA 衰变和角蛋白 1 的缺失，这在患者 1 的皮肤病变中得到了证实。在患者 1 的受累和未受累皮肤样本中均检测到角蛋白 2 的上调，而角蛋白 10 的蛋白丰度和分布模式保持不变。在患者 1 的手掌皮肤中，角蛋白 9 的异常和聚集染色模式。
KRT1 中的纯合“敲除”突变导致 EPPK 伴指节垫，而不是表皮松解性鱼鳞病。我们推测非肢端皮肤的保留可能是由于角蛋白 2 通过与角蛋白 10 形成异二聚体而上调的代偿作用。
