X-LINKED HYPOHIDROTIC ECTODERMAL DYSPLASIA (XHED) IN THE DOG

狗的 X 连锁少汗性外胚层发育不良 (XHED)

• 批准号: 7391956
• 负责人: MARGRET L CASAL
• 金额: $ 0.27万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7391956
• 关键词: LINKED; HYPOHIDROTIC; ECTODERMAL; DYSPLASIA; XHED

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The propositus was a male German Shepherd puppy with clinical and pathologic findings closely resembling anhidrotic/hypohidrotic X-linked ectodermal dysplasia (XHED) in man (McKusick, OMIM#305100). This X-linked recessive human disorder, occurring mainly in males, is characterized by skin and tooth abnormalities. Hair is sparse and there are missing and malformed teeth. Abnormalities in lacrimal glands may also be present. Skin biopsies show lack of pilosebaceous units. The lack of sweat glands in affected humans results in thermoregulatory problems that can be life threatening. While there have been reports in the veterinary literature of dogs with areas of baldness and tooth abnormalities resembling XHED in humans, studies were insufficient to define the mode of inheritance. From the propositus, we established a colony of dogs with XHED for the study of disease mechanisms and therapeutic trials. There is a complete lack of sweat glands (only present in footpads of normal dogs) and secondary hairs in the affected dogs. They are also completely hairless on their forehead, over the dorsal pelvic area, and the ventral thorax and abdomen. Most premolars and some incisors are missing and those teeth that are present are mostly conical in shape. As in human XHED, there is increased morbidity and mortality among XHED dogs compared to other dogs in the same environment. Most affected dogs have keratoconjunctivitis sicca, often accompanied by corneal ulceration, due to a decrease in lacrimal secretions, and frequent pneumonias due to a lack of serous glands in the respiratory tract. We have shown that a splice acceptor site mutation in intron 8 causes XHED in our dog model. The mutation results in a failure of transcription of the 3¿ end of EDA, thus leading to truncation of both isoforms of ectodysplasin (EDA), EDA1, and EDA2 rendering the resultant proteins inactive. A paper describing the mutation is currently in press. We have also completed our studies examining the systemic and local (pulmonary) immunity in the affected dogs in an effort to explain the frequent respiratory tract infections. A paper describing the results of this study is in press. The immune and mutational studies have also been presented at the annual meeting of the American Society of Human Genetics (2004). Our collaboration with APOXIS, S.A., a company that produces proteins for the treatment of cancers and rare genetic diseases, is still ongoing. Three litters of neonatal dogs have been treated with the recombinant protein and the effect on the development of sweat glands, hair follicles, teeth, tear production have been examined and a publication is in preparation describing the results. All of the histological samples were evaluated together with Dr. Elizabeth Mauldin, a board certified veterinary dermatologist and pathologist.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。委托对象是一只雄性德国牧羊犬幼犬，其临床和病理结果与人类无汗/少汗性 X 连锁外胚层发育不良 (XHED) 非常相似 (McKusick, OMIM#305100)。这种 X 连锁隐性人类疾病主要发生在男性中，其特征是皮肤和牙齿异常。头发稀疏，牙齿缺失且畸形。泪腺也可能存在异常。皮肤活检显示缺乏毛囊皮脂腺单位。受影响的人类缺乏汗腺会导致体温调节问题，从而危及生命。虽然兽医文献中有报道称，狗的秃毛区域和牙齿异常类似于人类的 XHED，但研究不足以定义遗传模式。根据该提案，我们建立了一个带有 XHED 的狗群，用于研究疾病机制和治疗试验。受影响的狗完全缺乏汗腺（仅存在于正常狗的足垫中）和次生毛发。它们的前额、背侧骨盆区域以及腹侧胸部和腹部也完全无毛。大多数前磨牙和一些门牙缺失，而现存的牙齿大多呈圆锥形。与人类 XHED 一样，与相同环境中的其他狗相比，XHED 狗的发病率和死亡率更高。大多数受影响的狗患有干燥性角结膜炎，由于泪液分泌减少，常常伴有角膜溃疡，并且由于呼吸道缺乏浆液腺而经常出现肺炎。我们已经证明，内含子 8 中的剪接受体位点突变会导致我们的狗模型中出现 XHED。该突变导致 EDA 3´ 末端转录失败，从而导致外胚增生蛋白 (EDA)、EDA1 和 EDA2 两种亚型截短，导致所得蛋白质失活。一篇描述该突变的论文目前正在出版。我们还完成了研究，检查受影响的狗的全身和局部（肺部）免疫力，以解释频繁的呼吸道感染。一篇描述这项研究结果的论文正在出版。免疫和突变研究也已在美国人类遗传学学会年会上发表（2004 年）。我们与 APOXIS, S.A.（一家生产用于治疗癌症和罕见遗传疾病的蛋白质的公司）的合作仍在继续。已经用重组蛋白治疗了三窝新生狗，并检查了其对汗腺、毛囊、牙齿发育、泪液产生的影响，并且正在准备一份出版物来描述结果。所有组织学样本均由经过委员会认证的兽医皮肤科医生和病理学家 Elizabeth Mauldin 博士一起评估。