01674-A: Molecular Basis of Congenital Hypothyroidism with Goiter in Spanish Water Dogs
Grant Status: Closed
Project SummaryRecently, congenital hypothyroidism with goiter (CHG) occurred in Spanish Water Dogs (SWD), a breed that was recognized by the AKC Foundation Stock Service in 2005 and approved for a variety of performance competitions in 2008. Hormones produced by the thyroid gland are crucially important for the health and development of dogs. Affected puppies exhibited mental dullness, dwarfism, enlarged thyroid glands, failure to suckle, and early death unless treated aggressively with thyroid hormone replacement. Even so, early diagnosis and treatment are only partially effective. The pattern of disease occurrence suggested autosomal recessive inheritance, and hormone testing of affected dogs indicated a problem of the thyroid gland itself. In collaboration with SWD breeders we undertook to determine the underlying mutation causing SWD congenital hypothyroidism and to provide a carrier test to be used to prevent future matings between carriers, while not selecting against desirable traits of the breed. SWD owners provided pedigree information, cheek brush samples for DNA isolation from affected, obligate carrier, and more distantly related dogs, and a piece of frozen affected dog thyroid tissue left over from a diagnostic biopsy. We used a "functional candidate gene" approach, first determining the enzymatic activity and presence of thyroid peroxidase (TPO) protein in affected and normal dog thyroids. TPO is crucial for thyroid hormone synthesis and is mutated in several cases of dog and human CHG. Neither TPO activity nor protein was detectable in the affected dog thyroid. Subsequently we amplified and sequenced TPO cDNA from the affected and normal dog thyroids. We determined that the affected dog was homozygous for a single guanine (G) insertion in a canid-specific portion of the gene that was incompatible with expression of the enzyme and, therefore, explained the disease. Obligate carriers in the SWD pedigree were heterozygous, as were 19 of 40 other clinically normal SWD tested. The disease mutation is the basis of a genetic carrier test conducted on cheek brush samples now offered to the public by the Laboratory of Comparative Medical Genetics at Michigan State University. Indications are that at least 2 dogs carrying the disease mutation have been imported from Europe and that carriers are distributed in a number of kennels. For more information on the test and/or to request a sampling kit, email email@example.com .
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