PDF(Pubmed)
Abstract：
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.
摘要：
掌plant角化病（PPK）是一种多面性皮肤病，其特征在于表皮增厚以及手掌和脚底的擦伤。在遗传原因中，FAM83G基因的双等位基因致病变异与狗和人类的PPK有关。这里,一种新的纯合变体(c.794G>C，p.Arg265Pro）在FAM83G基因中，通过对一名60岁女性PPK患者的全外显子组测序鉴定，据报道。患者表现出手脚皮肤的改变，营养不良的指甲，薄,卷曲而稀疏的头发，长的上眼睑睫毛，还有可怜的牙釉质.FAM83G通过与ser/thr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变体显示出较差的稳定性，与CK1α相互作用的丧失和减弱的WNT信号应答。这些缺陷在源自患者的皮肤成纤维细胞中持续存在。我们的发现暗示FAM83G-CK1α相互作用的丧失和随后WNT信号传导的减弱是由FAM83GR265P变体引起的PPK的发病机理的基础。
