Germline Mutations of TSH Receptor Gene as Cause of Nonautoimmune Subclinical Hypothyroidism

Abstract

Germline loss-of-function mutations of TSH receptor (TSHR) gene have been described in families with partial or complete TSH resistance. Large TSH elevations were generally found in the patients with homozygous or compound heterozygous mutations. In this study, we sequenced the entire TSHR gene in a series of 10 unrelated patients with slight (6.6-14.9 mU/liter) to moderate (24-46 mU/liter) elevations of serum TSH, associated with definitely normal free thyroid hormone concentrations. Thyroid volume was normal in all patients, except two with a modest hypoplasia. Autoimmune thyroid disease was excluded in all patients on the basis of clinical and biochemical parameters. Eight patients had at least one first-degree relative bearing the same biochemical picture. TSHR mutations were detected in 4 of 10 cases by analyzing DNA from peripheral leukocytes. A compound heterozygosity (P162A on maternal allele, and the novel mutation C600R on the paternal one) was found in the patient with the highest TSH levels. Only one TSHR allele was mutated in the remaining three cases, and no alterations in TSHR gene promoter were detected in all of these probands. A novel mutation (L467P) was detected on the maternal allele in one patient and in her monozygotic twin. Previously described inactive mutants, T655Delta and C41S, were detected in the other two cases. When tested on several occasions, circulating TSH values fluctuating above the upper limit of the normal range could be shown in heterozygous subjects of these families. A dominant mode of inheritance of the biochemical alterations was detected in these cases. Mutant TSHRs were studied during transient expression in COS7 and HEK293T cells. Their TSH-independent cAMP accumulation activities were very low or similar to mock-transfected cells, and no increases were seen after maximal hormone stimulation. Flow cytometry experiments showed a poor level of expression of all mutant TSHRs at the cell membrane. In conclusion, we found several loss-of-function mutations of TSHR, including two novel ones, in a series of unrelated patients with slightly elevated TSH levels. Therefore, partial resistance to TSH action is a frequent finding among patients with slight hyperthyrotropinemia of nonautoimmune origin. Germline mutations of TSHR may be associated with serum TSH values fluctuating above the upper limit of the normal range, also in the heterozygous state.

Prospective evaluation of the natural course of idiopathic subclinical hypothyroidism in childhood and adolescence

“…In this regard, the direct involvement of TSH receptor (TSHR) gene in the serum TSH concentration has been proven in some cases of SH, in which loss of function mutation has been identified (15,16). However, a low prevalence of TSHR mutations has been recently reported in children with SH (17).…”

Thyrotropin Receptor and Thyroid Transcription Factor-1 Genes Variant in Chinese Children with Congenital Hypothyroidism

“…After this report，many other mutations were discovered in patients with variable TSH unresponsiveness and different thyroid developmental status [2,[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. In some of these patients [3][4][5][6][7][8][9], TSH resistance was exemplified by normal free thyroid hormones with elevated TSH levels (defined as compensated hypothyroidism or subclinical hypothyroidism) and a normal or hypoplastic thyroid gland. Mild hypothyroidism was seen in four patients [10][11][12] with greatly elevated serum TSH associated with slightly low thyroid hormone levels and normal thyroid gland.…”

Severe post-partum autoimmune hypothyroidism associated with a novel loss-of-function mutation in intracellular domain of human thyrotropin receptor

“…The inactivating mutations of TSHR can account for several cases of non-autoimmune subclinical hypothyroidism, in particular those arising in familial settings. The cases detected in neonatal TSH screening were treated lifelong because hyperthyrotropinaemia is not transitory [17]. Cangul et al utilised genetic linkage analysis and direct sequencing to detect a homozygous nonsense mutation (R609X) in the case of congenital hypothyroidism.…”