CONGENITAL HYPOTHYROIDISM IN GIANT SCHNAUZERS

巨型雪纳瑞的先天性甲状腺功能减退症

• 批准号: 7391959
• 负责人: JOHN C FYFE
• 金额: $ 0.07万
• 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/7391959
• 关键词: CONGENITAL; HYPOTHYROIDISM; GIANT; SCHNAUZERS

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.

该主题项目是利用NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构是针对该中心的，这不是调查人员的机构。这些研究与约翰·费菲（John Fyfe）博士合作进行，在宾夕法尼亚大学（University of Pennsylvania）担任初级教职员工期间，自从他搬到密歇根州立大学的教职员工以来一直在继续。巨型Schnauzer狗报道了常染色体隐性非原主要甲状腺功能减少症（CH）。我们获得了这种疾病的载体，后来繁殖到正常的小猎犬。向后口气到Schnauzer线重现了该疾病。在原始报告时，犬甲状腺蛋白（TSH）的实验室测试尚无可用，尽管该疾病被认为不是甲状腺的主要疾病，但无法确定缺陷是垂体水平还是下丘脑的水平。对狗的TSH测试的可用性使我们能够解决这个问题。对F1-BackCross Matings产生的垃圾的前瞻性研究表明，在3至8周龄之间，受影响的狗垂体对甲状腺激素释放的马酮（TRH）无反应，可以外源性地给药或响应于对假设血氧血症的响应。面对甲状腺激素影响不足的幼崽不会产生TSH，这表明下丘脑 - 垂体轴无法更新TSH产生。 Fyfe博士与转诊中心合作，已经开始表征该疾病的分子基础。密歇根州立大学的Fyfe博士维持了具有这种疾病的主要殖民地，但转介中心向Fyfe博士提供了一个露出的女性，以增加CH Linkage家族的遗传异质性。 Fyfe博士获得了R03赠款，以确定该疾病的分子基础。脱落和反向交叉技术的结果表明，可能有一个以上的基因参与产生这种形式的先天性甲状腺功能减退症。遗传连锁研究消除了两个候选基因，即TRH受体和TSHB基因。我们目前正在研究TRH介导的信号传导级联反应中其他参与者的标记，以与该狗家族中的内分泌疾病相关。此外，与Henthorn博士合作，我们启动了一种基因组扫描以进行连锁，以开发比较的位置候选基因。已经发现了CFA 20。上述项目中获得的研究和知识直接为与甲虫在玩具狐狸犬狗中的甲虫一起对常染色体隐性CH的识别和表征提供了基础。这是一种严重的CH形式，导致矮人和在生命的前2周不壮成长。 Fyfe博士实验室的研究表明，受影响的狗甲状腺缺乏甲状腺过氧化物酶（TPO）活性，并且狗是TPO基因中胡说八道突变的纯合子。人类已经描述了类似的TPO突变。通过Fyfe博士实验室的测试计划确定的疾病携带者可用于建立繁殖菌落。