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

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。先证者是一只雄性德国牧羊犬，其临床和病理结果与人类无汗性/少汗性X连锁外胚层发育不良非常相似(McKusick，OMIM#305100)。这种X连锁隐性人类疾病主要发生在男性，以皮肤和牙齿异常为特征。头发稀疏，牙齿缺失和畸形。泪腺也可能出现异常。皮肤活检显示缺少毛囊皮脂腺单位。受影响的人缺乏汗腺，导致体温调节问题，可能危及生命。虽然在兽医文献中有关于狗的秃顶和牙齿异常区域类似于人类XHED的报告，但研究不足以定义遗传模式。从先证者开始，我们建立了一群患有XHED的狗，用于研究疾病机制和治疗试验。在受影响的狗身上，汗腺和次生毛完全缺乏(只出现在正常狗的脚垫上)。它们的前额、骨盆背部、胸腹和腹部也完全无毛。大多数前磨牙和一些门牙都不见了，现存的牙齿大多是圆锥形的。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都有所增加。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，经常伴有角膜溃疡，由于呼吸道缺乏浆液腺，经常发生肺炎。我们已经证明，在我们的狗模型中，内含子8的剪接受体位点突变导致了XHED。突变导致EDA的3‘端转录失败，从而导致EDA1和EDA2这两种异构体的胞外降解素(EDA)截断，从而使所产生的蛋白质失去活性。一篇描述这种突变的论文目前正在出版中。我们还完成了对受影响狗的全身和局部(肺)免疫的研究，以努力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中。免疫和突变研究也已在美国人类遗传学学会年会(2004年)上发表。我们与APOXIS，S.A.的合作仍在进行中，APOXIS，S.A.是一家生产治疗癌症和罕见遗传病的蛋白质的公司。已经用重组蛋白处理了三窝新生狗狗，并检查了对汗腺、毛囊、牙齿和泪液产生的影响，一份描述结果的出版物正在准备中。所有的组织样本都与委员会认证的兽医皮肤科医生和病理学家伊丽莎白·莫尔丁博士一起进行了评估。

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.