CONGENITAL HYPOTHYROIDISM IN GIANT SCHNAUZERS

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。这些研究是与约翰·法伊夫博士合作进行的，是在他担任初级教员期间在宾夕法尼亚大学根据这笔拨款开始的，在他转到密歇根州立大学教职后一直在继续。报道了巨型雪纳瑞犬常染色体隐性遗传性先天性甲状腺功能低下侏儒症。我们得到了一只这种疾病的携带者，随后将其培育成了一只正常的比格犬。对雪纳瑞线的回交复制了这种紊乱。在最初报告时，还没有犬促甲状腺激素(TSH)的实验室测试，虽然这种疾病被认为不是甲状腺的原发病，但无法确定缺陷是在脑垂体还是在下丘脑。对狗进行促甲状腺激素检测的可用性使我们能够解决这个问题。对F1回交后代的前瞻性研究表明，在3到8周大的时候，受影响的狗脑垂体会对促甲状腺激素释放激素(TRH)失去反应，促甲状腺激素释放激素(TRH)可以是外源性给药，也可以是内源性释放，以应对甲状腺功能低下症。面对无法检测的甲状腺激素，受影响的幼崽不会产生TSH，这表明下丘脑-脑垂体轴无法上调TSH的产生。Fyfe博士与转诊中心合作，已经开始研究这种疾病的分子基础。患有这种疾病的主要群体由密歇根州立大学的Fyfe博士维持，但由于CH连锁家族中遗传异质性的增加，参考中心向Fyfe博士提供了一名异交雌性。Fyfe博士获得了R03的拨款，以确定这种疾病的分子基础。异交和回交的结果表明，不止一个基因可能参与了这种形式的先天性甲状腺功能减退症的产生。遗传连锁研究已经排除了两个候选基因，TRH受体和TSHb基因。我们目前正在检查TRH介导的信号级联中其他参与者的基因标记，以寻找与这一家族狗的内分泌紊乱有关的因素。此外，在与亨索恩博士的合作下，我们已经启动了一项基因组扫描，以寻找连锁性，以便开发出比较的位置候选基因。免疫组织化学和电子显微镜检查的结果表明，促甲状腺激素细胞正在经历一种未折叠的蛋白质应激反应，可能是由于无法正确处理和包装TSH。上述研究和知识直接为最近在玩具狐狸犬中识别和鉴定常染色体隐性甲状腺肿提供了基础。这是一种严重的先天性心脏病，导致侏儒症和在生命的头两周无法茁壮成长。法菲·S博士实验室的研究表明，受影响的狗的甲状腺过氧化物酶(TPO)活性缺乏，并且TPO基因的无义突变是纯合子。类似的TPO突变在人类中也被描述过。通过Fyfe？S博士实验室的检测计划确定的疾病携带者可用于建立繁殖群体。

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. These studies, conducted in collaboration with Dr. John Fyfe, were begun under this grant at the University of Pennsylvania during the time he was a junior faculty member and have continued since his move to a faculty position at Michigan State University. Autosomal recessive non-primary, congenital hypothyroid dwarfism (CH) was reported in giant schnauzer dogs. We obtained a carrier of this disorder, which was subsequently bred to a normal beagle. Backcrosses to the schnauzer line reproduced the disorder. At the time of the original report, a laboratory test for canine thyrotropin (TSH) was not available and while the disorder was recognized not to be a primary disease of the thyroid, it was not possible to determine whether the defect lay at the level of the pituitary or the hypothalamus. The availability of a TSH test for the dog enabled us to resolve this question. Prospective studies of litters resulting from F1-backcross matings demonstrate that between 3 and 8 weeks of age the affected dog pituitary becomes unresponsive to thyrotropin releasing hormone (TRH), either administered exogenonously or produced endogenously in response to hypothyroxemia. In the face of undectedable thyroid hormone affected pups do not produce TSH, indicating an inability of the hypothalamic-pituitary axis to upregulate TSH production. Dr. Fyfe, in collaboration with the Referral Center, has begun to characterize the molecular basis of this disease. The main colony with this disorder is maintained by Dr. Fyfe at Michigan State University, but an outcross female was provided to Dr. Fyfe by the Referral Center to increased genetic heterogeneity in the CH linkage family. Dr. Fyfe received an R03 grant to determine the molecular basis of the disorder. Results of outcross and backcross matings suggest that more than one gene may be involved in producing this form of congenital hypothyroidism. Genetic linkage investigations have eliminated two gene candidates, the TRH receptor and TSHb genes. We are currently examining markers in genes of other participants in the TRH-mediated signaling cascade for association with the endocrine disorder in this family of dogs. Additionally, in collaboration with Dr. Henthorn we have initiated a genome scan for linkage in order to develop comparative positional candidate genes. Tentative linkage has been found to CFA 20. Results of immunohistochemical and electron microscopic examination of affected dog pituitary glands suggest that the thyrotrophs are experiencing an unfolded protein stress response, perhaps due to inability to properly process and package TSH. The studies and knowledge gained in the above project directly provided the basis for the recent recognition and characterization of autosomal recessive CH with goiter in toy fox terrier dogs. This is a severe form of CH causing dwarfism and failure to thrive in the first 2 weeks of life. Studies in Dr. Fyfe¿s laboratory demonstrated that affected dog thyroid is deficient in thyroid peroxidase (TPO) activity, and the dogs are homozygous for a nonsense mutation in the TPO gene. Similar TPO mutations have been described in humans. Carriers of the disorder identified through a testing program in Dr. Fyfe¿s laboratory are available for establishment of a breeding colony.