PDF(Pubmed)
Abstract：
Recessive dystrophic epidermolysis bullosa is a rare genodermatosis caused by a mutation of the Col7a1 gene. The Col7a1 gene codes for collagen type VII protein, a major component of anchoring fibrils. Mutations of the Col7a1 gene can cause aberrant collagen type VII formation, causing an associated lack or absence of anchoring fibrils. This presents clinically as chronic blistering, scarring, and fibrosis, often leading to the development of cutaneous squamous cell carcinoma. Patients also experience persistent pain and pruritus. Pain management and supportive bandaging remain the primary treatment options. The pathology of recessive dystrophic epidermolysis bullosa was first described in the 1980s, and there has since been a multitude of encouraging treatment options developed. However, in vivo research has been hindered by inadequate models of the disease. The various mouse models in existence possess longevity and surface area constraints, or do not adequately model a normal human disease state. In this paper, we describe a novel rat model of recessive dystrophic epidermolysis bullosa that offers an alternative to previous murine models. An 8-base pair deletion was induced in the Col7a1 gene of Lewis rats, which was subsequently found to cause a premature stop codon downstream. Homozygous mutants presented with a fragile and chronically blistered phenotype postnatally. Further histological analysis revealed subepidermal clefting and the absence of anchoring fibrils. The generation of this novel model offers researchers an easily maintained organism that possesses a larger surface area for experimental topical and transfused therapies to be tested, which may provide great utility in the future study of this debilitating disease.
摘要：
隐性营养不良性大疱性表皮松解症是由Col7a1基因突变引起的罕见遗传性皮肤病。Col7a1基因编码VII型胶原蛋白,锚定原纤维的主要成分。Col7a1基因的突变可导致VII型胶原的异常形成，导致相关的缺乏或缺乏锚定原纤维。这在临床上表现为慢性起泡，疤痕,和纤维化，经常导致皮肤鳞状细胞癌的发展。患者还经历持续性疼痛和瘙痒。疼痛管理和支持性包扎仍然是主要的治疗选择。隐性营养不良性大疱性表皮松解症的病理最早是在1980年代描述的，此后，开发了许多令人鼓舞的治疗方案。然而,体内研究受到疾病模型不足的阻碍。存在的各种小鼠模型具有寿命和表面积限制，或者没有充分模拟正常的人类疾病状态。在本文中,我们描述了一种新的隐性营养不良性大疱性表皮松解症大鼠模型，该模型为以前的小鼠模型提供了替代方法。在Lewis大鼠的Col7a1基因中诱导了8个碱基对的缺失，随后发现导致下游过早终止密码子。纯合突变体在出生后表现出脆性和慢性起泡的表型。进一步的组织学分析显示表皮下裂开，并且没有锚定原纤维。这种新型模型的产生为研究人员提供了一种易于维护的生物体，该生物体具有更大的表面积，可用于实验局部和输血疗法进行测试。这可能在未来对这种使人衰弱的疾病的研究中提供巨大的效用。
