Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Exp Dermatol. 2017 Nov;26(11):1134-1136. doi: 10.1111/exd.13363. Epub 2017 Jul 27.
Mutations in SLURP1, a secreted protein of keratinocytes, cause a palmoplantar keratoderma (PPK) known as mal de Meleda. Slurp1 deficiency in mice faithfully recapitulates the human disease, with increased keratinocyte proliferation and thickening of the epidermis on the volar surface of the paws. There has long been speculation that SLURP1 serves as a ligand for a receptor that regulates keratinocyte growth and differentiation. We were intrigued that mutations leading to increased signalling through the epidermal growth factor receptor (EGFR) cause PPK. Here, we sought to determine whether reducing EGFR signalling would ameliorate the PPK associated with SLURP1 deficiency. To address this issue, we bred Slurp1-deficient mice that were homozygous for a hypomorphic Egfr allele. The hypomorphic Egfr allele, which leads to reduced EGFR signalling in keratinocytes, did not ameliorate the PPK elicited by SLURP1 deficiency, suggesting that SLURP1 deficiency causes PPK independently (or downstream) from the EGFR pathway.
SLURP1 是一种角蛋白细胞分泌的蛋白，其基因突变会导致掌跖角化病（PPK），即梅勒达病。小鼠 SLURP1 缺陷能忠实再现人类疾病，表现为掌跖屈面的角蛋白细胞增殖和表皮增厚。长期以来，人们一直推测 SLURP1 是一种配体，能调节角蛋白细胞的生长和分化。导致表皮生长因子受体（EGFR）信号通路过度激活的基因突变会引起 PPK，这一点引发了我们的关注。在此，我们试图确定降低 EGFR 信号是否能改善 SLURP1 缺陷相关的 PPK。为解决这个问题，我们培育了 SLURP1 缺陷纯合子小鼠，其携带一个 EGFR 功能减弱的等位基因。该 EGFR 功能减弱的等位基因导致角蛋白细胞中的 EGFR 信号降低，但未能改善由 SLURP1 缺陷引起的 PPK，这表明 SLURP1 缺陷引起的 PPK 不依赖于（或下游于）EGFR 通路。
