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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。先证者是一只雄性德国牧羊犬幼犬，其临床和病理学发现与人类无汗/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，其特征是皮肤和牙齿异常。头发稀疏，牙齿缺失和畸形。泪腺中也可能存在脱落细胞。皮肤活检显示缺乏毛囊皮脂腺单位。受影响的人缺乏汗腺会导致可能危及生命的体温调节问题。虽然在兽医文献中有报告称，狗的秃顶和牙齿异常的区域类似于人类的XHED，但研究不足以确定遗传模式。从先证者出发，我们建立了一个XHED犬群，用于疾病机制和治疗试验的研究。有一个完全缺乏汗腺（只存在于正常狗的脚垫）和二级毛在受影响的狗。它们的前额、背侧骨盆区、腹侧胸部和腹部也完全无毛。大多数前臼齿和一些门牙缺失，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犬相比，XHED犬的发病率和死亡率增加。大多数受影响的犬患有干燥性角结膜炎，通常伴有角膜溃疡，这是由于泪液分泌减少，以及由于呼吸道中缺乏浆液性腺体而导致的频繁肺炎。我们已经证明，在我们的狗模型中，内含子8中的剪接受体位点突变导致XHED。该突变导致EDA的3 ′端转录失败，从而导致外胚层发育不良（EDA）的两种同种型（EDA 1和EDA 2）的截短，使所得蛋白失活。一篇描述这种突变的论文目前正在出版中。我们还完成了研究，检查了受影响犬的全身和局部（肺部）免疫力，以解释频繁的呼吸道感染。一份描述这项研究结果的论文正在印刷中。免疫和突变研究也已在美国人类遗传学会年会（2004年）上发表。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仍在进行中。用重组蛋白处理了三窝新生犬，并检查了对汗腺、毛囊、牙齿、泪液产生发育的影响，正在编写描述结果的出版物。所有组织学样本均与委员会认证的兽医皮肤科医生和病理学家Elizabeth Mauldin博士一起进行评价。

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.