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。这些研究是与约翰·法伊夫博士合作进行的，在他还是一名初级教员的时候，就在宾夕法尼亚大学的这项资助下开始了，自从他搬到密歇根州立大学担任教员以来，这些研究一直在继续。常染色体隐性遗传的非原发性，先天性甲状腺功能减退性侏儒症（CH）的报告，在巨大的雪纳瑞犬。我们获得了这种疾病的携带者，随后将其培育成正常的比格犬。回交到雪纳瑞系再现了这种紊乱。在最初报告时，未进行犬促甲状腺激素（TSH）的实验室检查，虽然该疾病被认为不是甲状腺原发性疾病，但无法确定缺陷是否位于垂体或下丘脑水平。对狗进行TSH测试的可用性使我们能够解决这个问题。对F1回交交配产生的窝仔进行的前瞻性研究表明，在3至8周龄之间，受影响的犬垂体对促甲状腺激素释放激素（TRH）无反应，无论是外源性给药还是内源性产生，以应对甲状腺功能低下症。在面对无法检测的甲状腺激素影响的幼崽不产生TSH，表明下丘脑-垂体轴无法上调TSH的生产。Fyfe博士与转诊中心合作，已经开始描述这种疾病的分子基础。 这种疾病的主要群体由密歇根州立大学的Fyfe博士维持，但转介中心向Fyfe博士提供了一只异交雌性，以增加CH连锁家族的遗传异质性。Fyfe博士获得了R 03资助，以确定这种疾病的分子基础。异交和回交交配的结果表明，一个以上的基因可能参与产生这种形式的先天性甲状腺功能减退症。遗传连锁研究已经排除了两个候选基因，TRH受体和TSHb基因。我们目前正在研究TRH介导的信号级联反应中其他参与者的基因标记，以确定其与该犬家族内分泌紊乱的关系。此外，我们与Henthorn博士合作，启动了一项基因组扫描，以寻找连锁，从而开发出比较位置的候选基因。已发现与CFA 20的初步联系。受影响的狗垂体的免疫组化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个未折叠的蛋白应激反应，可能是由于无法正确的处理和包装TSH。 上述研究和知识的获得，直接提供了最近的识别和表征的常染色体隐性遗传性甲状腺肿的玩具猎狐犬CH的基础。这是一种严重形式的CH，导致侏儒症，并在生命的前2周内无法茁壮成长。在法伊夫博士的研究的实验室证明，受影响的狗甲状腺是缺乏甲状腺过氧化物酶（TPO）的活动，狗是纯合子的无义突变的TPO基因。类似的TPO突变已在人类中描述。通过Fyfe博士实验室的一个测试项目确定的这种疾病的携带者可以建立一个繁殖群体。