Genetic basis - The disease is caused by a homozygous recessive mutation in the thyroid peroxidase (TPO) gene. The causative mutation is a single guanosine insertion (c.39_40insG) in exon 1 of the TPO gene. TPO is essential for thyroid hormone synthesis by catalyzing iodide organification. Mutation results in loss of TPO activity, leading to inability to produce thyroid hormones.
Pathophysiology - Affected puppies have thyroid hormone deficiency (hypothyroidism) from birth. Thyroid glands undergo hypertrophy and hyperplasia due to persistent thyroid-stimulating hormone (TSH) stimulation, resulting in goiter. Clinical symptoms appear within 1-2 weeks after birth when maternal thyroid hormone protection is lost. Signs include growth retardation, dwarfism, delayed opening of eyes and ear canals, delayed teething, and poor coat quality. Some puppies may die early if not treated.
Inheritance - Autosomal recessive inheritance. Dogs with two copies of the mutated gene (P/P) are affected. Carriers (N/P) are asymptomatic but can pass the mutation to offspring. Clear dogs (N/N) do not carry or transmit the mutation.
Why This Matters to Breeders and Vets - Breeders: Genetic testing allows identification of carriers and prevents mating that could produce affected puppies. Vets: Early diagnosis and thyroid hormone replacement therapy improve survival and quality of life. Untreated puppies have poor prognosis.