Somatic mutations of the thyroid-stimulating hormone receptor gene in feline hyperthyroidism: parallels with human hyperthyroidism

Abstract

Hyperthyroidism is the most common endocrinopathy in cats, and is both clinically and histopathologically very similar to human toxic nodular goitre (TNG). Molecular studies on human TNG have revealed the presence of mis-sense mutations in the thyroid-stimulating hormone receptor (TSHR) gene, most frequently in exon 10. Our hypothesis was that similar mutations exist in hyperthyroid cats. Genomic DNA was extracted from 134 hyperplastic/ adenomatous nodules (from 50 hyperthyroid cats), and analysed for the presence of mutations in exon 10 of the TSHR gene. 11 different mutations were detected, one silent and 10 mis-sense, of which nine were somatic mutations. 28 of the 50 cats (67/134 nodules) had at least one mis-sense mutation. The mis-sense mutations were Met-452<Thr in 17 cats (35 nodules), Ser-504<Arg (two different mutational forms) in two cats (two nodules), Val-508<Arg in one cat (three nodules), Arg-530<Gln in one cat (two nodules), Val-557<Leu in 13 cats (36 nodules), Thr-631<Ala or Thr-631<Phe (each mutation seen in one nodule of one cat), Asp-632<Tyr in six cats (10 nodules) and Asp-632<His in one cat (one nodule). Five of these mutations have been associated previously with human hyperthyroidism. Of the 41 cats for which more than one nodule was available, 14 had nodules with different mutations. The identification of a potential genetic basis for feline hyperthyroidism is novel, increases our understanding of the pathogenesis of this significant feline disease, and confirms its similarity to TNG.

ANIMAL MODELS OF DISEASE: Feline hyperthyroidism: an animal model for toxic nodular goiter

“…Not all nodules taken from an individual cat or thyroid lobe showed the same mutations, with different mutations appearing in different adenomas and hyperplastic nodules (Watson et al 2005). A similar scenario has been found in human hyperthyroidism (Fuhrer et al 1996, Holzapfel et al 1997, Tonacchera et al 1998.…”

“…In hyperthyroid cats, early studies carried out in small numbers of cats failed to identify any TSHR mutations (Pearce et al 1997, Peeters et al 2002. However, a later detailed study of 134 nodules from 50 hyperthyroid cats found ten missense mutations, of which five have previously been associated with human hyperthyroidism (Watson et al 2005). The most common TSHR mutation detected in cats is Met452-Thr (a substitution of methionine by threonine), which is analogous to the human mutation Met453-Thr observed in sporadic human nodular goiter , Nishihara et al 2009).…”

“…As noted earlier, mutations in the TSHR gene and the alpha subunit of the G s protein have been documented in both human and feline toxic nodular goiter. These findings suggest that these gene mutations play a role in the disease; however, the finding of such a gene mutation does not always equate to a functional defect leading to hyperthyroidism (Derwahl et al 1996, Fuhrer et al 1996, Watson et al 2005.…”

Subclinical Hyperthyroidism in Cats: A Spontaneous Model of Subclinical Toxic Nodular Goiter in Humans?

“…In 96% of cases, feline hyperthyroidism is associated with a unilateral or bilateral nodular goiter caused by true adenomas or nodular hyperplasia of the thyroid, and these histopathological changes are similar to those found in human toxic nodular goiter (6,7). Although early work failed to find TSH receptor mutations in relatively small numbers of feline hyperthyroid glands (*n ¼ 10) (8,9), a detailed study of 134 nodules from 50 hyperthyroid cats found 10 missense mutations of which 5 have previously been associated with human hyperthyroidism (10). In addition, altered expression of inhibitory and stimulatory Gproteins has been found in hyperthyroid cats (8,11).…”

Prevalence of TSH Receptor and Gs.ALPHA. Mutations in 45 Autonomously Functioning Thyroid Nodules in Japan

“…Thereafter, several groups reported 4 TSHR mutations (Met453Thr, Ile486Met, Leu512Arg, and Table 4. Clinical characteristics in patients without TSHR and Gsα mutations in AFTN due is the most common (34%) TSHR mutation [27]. Several studies of human AFTN also observed a relatively high prevalence of Met453Thr, which was not explained by iodine intake [10,15].…”