Modeling AEC-New approaches to study rare genetic disorders.
Modeling AEC-New approaches to study rare genetic disorders.
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DOI：
10.1002/ajmg.a.36455
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发表时间：
2014-10
期刊：
影响因子：
--
通讯作者：
Koster MI
中科院分区：
文献类型：
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作者：
Koch PJ;Dinella J;Fete M;Siegfried EC;Koster MI
强直性睑裂-外胚层缺陷-唇腭裂（AEC）综合征是一种罕见的单基因疾病，其特征是外胚层衍生组织（如皮肤及其附件）的严重异常。患病婴儿发病的一个主要原因是严重和慢性皮肤糜烂。目前，支持性治疗是AEC患者唯一可用的治疗选择。TP 63是一种编码表皮发育关键调节因子的基因，其突变是AEC的遗传原因。然而，目前尚不清楚TP 63突变如何导致患者皮肤中出现的各种缺陷。在这篇综述中，我们将讨论目前的知识AEC疾病的机制，通过研究患者的组织和基因工程小鼠模型，旨在模仿方面的障碍。然后，我们将专注于AEC模型的新方法，包括使用患者细胞和干细胞技术在人体组织培养模型中复制疾病。后一种方法将促进我们对这种疾病的理解，并将允许开发新的体外系统，以确定治疗AEC患者皮肤糜烂的药物。此外，使用干细胞技术，特别是诱导多能干细胞（iPSC），将使研究人员能够开发新的治疗方法，在纠正致病突变后使用患者自己的细胞（自体角质形成细胞移植）治疗疾病。
Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is a rare monogenetic disorder that is characterized by severe abnormalities in ectoderm-derived tissues, such as skin and its appendages. A major cause of morbidity among affected infants is severe and chronic skin erosions. Currently, supportive care is the only available treatment option for AEC patients. Mutations in TP63, a gene that encodes key regulators of epidermal development, are the genetic cause of AEC. However, it is currently not clear how mutations in TP63 lead to the various defects seen in the patients’ skin. In this review, we will discuss current knowledge of the AEC disease mechanism obtained by studying patient tissue and genetically engineered mouse models designed to mimic aspects of the disorder. We will then focus on new approaches to model AEC, including the use of patient cells and stem cell technology to replicate the disease in a human tissue culture model. The latter approach will advance our understanding of the disease and will allow for the development of new in vitro systems to identify drugs for the treatment of skin erosions in AEC patients. Further, the use of stem cell technology, in particular induced pluripotent stem cells (iPSC), will enable researchers to develop new therapeutic approaches to treat the disease using the patient’s own cells (autologous keratinocyte transplantation) after correction of the disease-causing mutations.