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.
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