CONGENITAL HYPOTHYROIDISM IN GIANT SCHNAUZERS

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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.