来自掌跖角化症患者的一种新型 FAM83G 变体通过 FAM83G-CK1α 相互作用的丧失破坏 WNT 信号传导。
A novel FAM83G variant from palmoplantar keratoderma patient disrupts WNT signalling via loss of FAM83G-CK1α interaction.
发表日期：2024 Jul
作者：
Lorraine Glennie, Marta Codina Solà, Mar Xunclà, Gloria Aparicio Español, Elena Garcia-Arumí, Eduardo Fidel Tizzano, Nicola T Wood, Thomas J Macartney, Amaia Lasa-Aranzasti, Gopal P Sapkota
来源：
Open Biology
摘要：
掌跖角化病 (PPK) 是一种多方面的皮肤病，其特征是表皮增厚以及手掌和脚底擦伤。在遗传原因中，FAM83G 基因的双等位基因致病性变异与狗和人类的 PPK 相关。在此，报道了 FAM83G 基因中的一个新的纯合变异（c.794G>C，p.Arg265Pro），该变异是通过对一名 60 岁女性 PPK 患者的全外显子组测序鉴定的。患者表现出双手和足部皮肤改变，指甲营养不良，头发稀疏、卷曲和稀疏，上眼睑睫毛过长，牙釉质较差。 FAM83G 通过与丝氨酸/苏氨酸蛋白激酶 CK1α 结合激活 WNT 信号传导。当在 FAM83G-/- DLD1 结直肠癌细胞中表达时，FAM83GR265P 变体表现出稳定性差、与 CK1α 相互作用丧失以及 WNT 信号反应减弱。这些缺陷在来自患者的皮肤成纤维细胞中持续存在。我们的研究结果表明，FAM83G-CK1α 相互作用的丧失以及随后 WNT 信号传导的减弱是 FAM83GR265P 变异引起的 PPK 发病机制的基础。
Palmoplantar keratoderma (PPK) is a multi-faceted skin disorder characterized by the thickening of the epidermis and abrasions on the palms and soles of the feet. Among the genetic causes, biallelic pathogenic variants in the FAM83G gene have been associated with PPK in dogs and humans. Here, a novel homozygous variant (c.794G>C, p.Arg265Pro) in the FAM83G gene, identified by whole exome sequencing in a 60-year-old female patient with PPK, is reported. The patient exhibited alterations in the skin of both hands and feet, dystrophic nails, thin, curly and sparse hair, long upper eyelid eyelashes, and poor dental enamel. FAM83G activates WNT signalling through association with ser/thr protein kinase CK1α. When expressed in FAM83G-/- DLD1 colorectal cancer cells, the FAM83GR265P variant displayed poor stability, a loss of interaction with CK1α and attenuated WNT signalling response. These defects persisted in skin fibroblast cells derived from the patient. Our findings imply that the loss of FAM83G-CK1α interaction and subsequent attenuation of WNT signalling underlie the pathogenesis of PPK caused by the FAM83GR265P variant.