Division of Clinical Dermatology, Department of Clinical Veterinary Science, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
DermFocus, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
PLoS One. 2020 Mar 2;15(3):e0225901. doi: 10.1371/journal.pone.0225901. eCollection 2020.
Hereditary nasal parakeratosis (HNPK) is an inherited disorder described in Labrador Retrievers and Greyhounds. It has been associated with breed-specific variants in the SUV39H2 gene encoding a histone 3 methyltransferase involved in epigenetic silencing. Formalin-fixed biopsies of the nasal planum of Labrador Retrievers were screened by immunofluorescence microscopy for the presence and distribution of epidermal proliferation and differentiation markers. Gene expression of these markers was further analysed using RNA sequencing (RNA-seq) and ultrastructural epidermal differences were investigated by electron microscopy. Differentiation of the nasal planum in the basal and suprabasal epidermal layers of HNPK-affected dogs (n = 6) was similar compared to control dogs (n = 6). In the upper epidermal layers, clear modifications were noticed. Loricrin protein was absent in HNPK-affected nasal planum sections in contrast to sections of the same location of control dogs. However, loricrin was present in the epidermis of paw pads and abdominal skin from HNPK dogs and healthy control dogs. The patterns of keratins K1, K10 and K14, were not markedly altered in the nasal planum of HNPK-affected dogs while the expression of the terminal differentiation marker involucrin appeared less regular. Based on RNA-seq, LOR and IVL expression levels were significantly decreased, while KRT1, KRT10 and KRT14 levels were up-regulated (log2fold-changes of 2.67, 3.19 and 1.71, respectively) in HNPK-affected nasal planum (n = 3) compared to control dogs (n = 3). Electron microscopical analysis revealed structural alterations in keratinocytes and stratum corneum, and disrupted keratinocyte adhesions and distended intercellular spaces in lesional samples (n = 3) compared to a sample of a healthy control dog (n = 1). Our findings demonstrate aberrant keratinocyte terminal differentiation of the nasal planum of HNPK-affected Labrador Retrievers and provide insights into biological consequences of this inactive SUV39H2 gene variant.
遗传性鼻角化过度症（HNPK）是一种在拉布拉多猎犬和格雷伊猎犬中描述的遗传性疾病。它与 SUV39H2 基因的种特异性变异有关，该基因编码一种组蛋白 3 甲基转移酶，参与表观遗传沉默。通过免疫荧光显微镜筛选拉布拉多猎犬鼻平面的福尔马林固定活检，以检测表皮增殖和分化标志物的存在和分布。使用 RNA 测序（RNA-seq）进一步分析这些标记物的基因表达，并通过电子显微镜研究超微结构表皮差异。HNPK 受影响犬（n=6）鼻平面的基底和基底上层的分化与对照犬（n=6）相似。在上表皮层，注意到明显的变化。与对照犬相同位置的鼻平面切片相比，HNPK 受影响鼻平面切片中缺乏丝聚蛋白蛋白。然而，HNPK 犬和健康对照犬的爪垫和腹部皮肤的表皮中存在丝聚蛋白。在 HNPK 受影响犬的鼻平面中，角蛋白 K1、K10 和 K14 的模式没有明显改变，而终末分化标记物 Involucrin 的表达似乎不那么规则。基于 RNA-seq，LOR 和 IVL 的表达水平显著降低，而 KRT1、KRT10 和 KRT14 的水平上调（分别为 2.67、3.19 和 1.71 的对数倍变化）在 HNPK 受影响的鼻平面（n=3）与对照犬（n=3）相比。电子显微镜分析显示，病变样本（n=3）与健康对照犬样本（n=1）相比，角质形成细胞和角质层的结构发生改变，角质形成细胞黏附破坏，细胞间隙膨胀。我们的研究结果表明，HNPK 受影响的拉布拉多猎犬鼻平面的角质形成细胞终末分化异常，并为这种 SUV39H2 基因变异的无活性提供了生物学后果的见解。
