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. Congenital hypothyroidism may either be caused by dysmorphogenesis of the thyroid gland (hypo- or aplasia) or by dyshormonogenesis associated with a goiter. Disorders in hormonogenesis include the inability of the thyroid to concentrate iodide, thyroglobulin deficiency, and organification defects caused by thyroid peroxidase deficiency. Congenital hypothyroidism has been described in humans and animals, including sporadic feline cases. We have studied the clinical features, endocrine and biochemical abnormalities, pathologic findings, and breeding studies of a family of domestic shorthair cats with primary congenital hypothyroidism. Month-old male and female littermates failed to thrive, had coarse facial features, stunted growth with shortened body length, and appeared constipated and dull. Bone growth was markedly delayed for the age of the animals. A diagnosis of hypothyroidism was reached based upon low serum T3 and T4 concentrations and a response to thyroxin treatment. The affected male and mother were bred which resulted in affected kittens, whereas, when out-crossed to healthy unrelated animals no affected kittens were produced. Breeding two healthy offspring of the affected cat also produced affected kittens. All affected kittens had a congenital goiter with thyroid glands of the original affected cat measuring 5 x 2 x 2 cm each and weighing 6.6 and 5.72 g despite 2 years of treatment The thyroid glands were markedly hypercellular revealing few open follicles and minimal colloid production. Immunohistochemistry was consistent with thyroid hyperplasia of follicular epithelial cells. Serum T3, free, and total T4 concentrations of affected cats were consistently low/unmeasurable, whereas serum thyroid stimulating hormone (TSH) levels were high from the first days of life when compared to healthy cats. There was no thyroid peroxidase activity in thyroid tissue from affected cats, whereas normal thyroids showed iodide oxidation activity of 1.04 0.59 U/mg protein. In this family of domestic shorthair cats, congenital hypothyroidism with goiter was caused by a complete thyroid peroxidase deficiency and is inherited as an autosomal recessive trait. Molecular studies are underway to determine the genetic basis for the disease in this feline model. The clinical and pathologic features, endocrine basis, and mode of inheritance are homologues to the disorder seen in humans and dogs. This disease model may offer opportunities to assess the intrauterine effects of thyroid hormone, gene transfer to the thyroid gland and stem cell therapy. We are also studying two dwarf, retarded Golden retriever littermates with hypothyroidism due to a TSH deficiency suggestive of a pituitary defect. These additional disease models may offer a better understanding of the entire endocrine axis for the thyroid hormone in this species.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Animal (Mammalian and Nonmammalian) Model, and Animal and Biological Material Resource Grants (P40)
Project #
Application #
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Schools of Veterinary Medicine
United States
Zip Code
Lok, J B; Shao, H; Massey, H C et al. (2017) Transgenesis in Strongyloides and related parasitic nematodes: historical perspectives, current functional genomic applications and progress towards gene disruption and editing. Parasitology 144:327-342
Casal, Margret L; Wang, Ping; Mauldin, Elizabeth A et al. (2017) A Defect in NIPAL4 Is Associated with Autosomal Recessive Congenital Ichthyosis in American Bulldogs. PLoS One 12:e0170708
Mauldin, Elizabeth A; Wang, Ping; Olivry, Thierry et al. (2017) Epidermolysis bullosa simplex in sibling Eurasier dogs is caused by a PLEC non-sense variant. Vet Dermatol 28:10-e3
Gurda, Brittney L; De Guilhem De Lataillade, Adrien; Bell, Peter et al. (2016) Evaluation of AAV-mediated Gene Therapy for Central Nervous System Disease in Canine Mucopolysaccharidosis VII. Mol Ther 24:206-216
Nicoli, Elena-Raluca; Al Eisa, Nada; Cluzeau, Celine V M et al. (2016) Defective Cytochrome P450-Catalysed Drug Metabolism in Niemann-Pick Type C Disease. PLoS One 11:e0152007
Hunt, Vicky L; Tsai, Isheng J; Coghlan, Avril et al. (2016) The genomic basis of parasitism in the Strongyloides clade of nematodes. Nat Genet 48:299-307
Mohandas, Namitha; Hu, Min; Stroehlein, Andreas J et al. (2016) Reconstruction of the insulin-like signalling pathway of Haemonchus contortus. Parasit Vectors 9:64
Tritschler, Claudia; Mizukami, Keijiro; Raj, Karthik et al. (2016) Increased erythrocytic osmotic fragility in anemic domestic shorthair and purebred cats. J Feline Med Surg 18:462-70
Flanagan-Steet, Heather; Aarnio, Megan; Kwan, Brian et al. (2016) Cathepsin-Mediated Alterations in TGFß-Related Signaling Underlie Disrupted Cartilage and Bone Maturation Associated With Impaired Lysosomal Targeting. J Bone Miner Res 31:535-48
Albarqi, Mennatallah M Y; Stoltzfus, Jonathan D; Pilgrim, Adeiye A et al. (2016) Regulation of Life Cycle Checkpoints and Developmental Activation of Infective Larvae in Strongyloides stercoralis by Dafachronic Acid. PLoS Pathog 12:e1005358

Showing the most recent 10 out of 316 publications