Molecular Genetic Characterization of Thyroid Dyshormonogenesis in a French Bulldog

Abstract

BackgroundA case of congenital hypothyroidism with goiter (CHG) in a juvenile French bulldog was identified and hypothesized to be caused by dyshormonogenesis of genetic etiology.ObjectivesTo describe case management, unusual phenotypic aspects, and a CHG‐causing mutation in a French bulldog.AnimalsThyroid tissue and blood from a CHG‐affected French bulldog and 4 normal control dogs and buccal brush samples of 125 French bulldogs were studied.MethodsStandard clinical assessment and laboratory tests were applied. Thyroid peroxidase (TPO) iodide oxidation activity was measured in vitro, and TPO protein was assessed on Western blots. Thyroid peroxidase exons and flanking splice sites were amplified from genomic DNA and sequenced. Thyroid peroxidase cDNA was amplified from thyroid RNA and sequenced.ResultsAt 9 months of age, the affected dog had signs of cretinism, but near‐normal skeletal maturation. The enlarged thyroid glands exhibited noninflammatory fibrosis and aberrant follicular organization. Thyroid peroxidase activity and immunocrossreactive protein were undetectable. There was a T>C mutation of the intron 12 splice donor consensus that caused abnormally spliced mRNA, consistent with absent TPO function. The mutant allele was not observed in 125 clinically normal French bulldogs.ConclusionsPresumptive CHG in a French bulldog with unusual clinical presentation is described. Genetic etiology was confirmed by identifying the underlying TPO mutation.

Association of recessive c.430G>A (p.(Gly144Arg)) thyroid peroxidase variant with primary congenital hypothyroidism in cats

“…[1][2][3]40,41 In literature, decreased TPO activity leading to dyshormonogenesis in a cat has been confirmed with biochemical studies. 42 In addition, variants in this gene were already described in cats 20 and dogs [43][44][45][46][47] with similar clinical features, and in many human patients 40,41 with a similar defect. In humans, severe CH with a total iodide organification defect is typically caused by variants in TPO (thyroid peroxidase, involved in iodide organification and thyronine coupling), while mild CH with a partial iodide organification defect is typically caused by variants in DUOX2 (dual oxydase, involved in peroxide production required for iodide organification), DUOXA2 (accessory protein for DUOX2) and SLC26A4 (pendrin, an anion transporter involved in apical iodide efflux).…”

Clinical and magnetic resonance imaging findings in a French bulldog puppy with genetically confirmed congenital hypothyroidism

“…Congenital hypothyroidism with goiter in dogs is commonly caused by an inborn error of thyroid hormone synthesis (dyshormonogenesis) 3 . Breed‐specific mutations in the thyroid peroxidase (TPO) gene causing CHG are described in Toy Fox Terriers, 4 Rat Terriers, 5 Tenterfield Terriers, 2 and Spanish Water dogs and French Bulldogs 6,7 ; in addition, a sodium/iodide symporter mutation is described in a family of Shih‐Tzu dogs 8 …”