Thyrotropin receptor gene mutations and TSH resistance: variable expressivity in the heterozygotes

Clin Endocrinol (Oxf). 2005 Aug;63(2):146-51. doi: 10.1111/j.1365-2265.2005.02314.x.


Objective: TSH resistance ranges from overt nonautoimmune hypothyroidism to subclinical hypothyroidism, defined as mild hyperthyrotrophinaemia but a euthyroid state clinically. To date, 23 inactivating mutations of the TSH receptor (TSHR) gene have been proven responsible for the clinical condition, but an absence of mutations in the TSHR gene has been reported for several cases of TSH resistance as well. In this paper, we aimed to investigate the actual role of the TSHR gene in the development of both subclinical and congenital hypothyroidism.

Patients: 14 hypothyroid newborns, 116 subclinical hypothyroid subjects and 120 healthy controls.

Measurements: Through denaturing high performance liquid chromatography (DHPLC), we screened for mutations the TSHR gene (the proximal promoter, the exons and their flanking regions), and evaluated the association between serum TSH and functionally characterized alleles identified.

Results: In the hypothyroid patients, one patient was heterozygous for a new missense variation, E34K, whereas two others patients were either homozygous or heterozygous for the P162A substitution. In the subclinical hypothyroid subjects, we detected only heterozygous substitutions: they are mostly new (123-124insTGCA, P27T, R46P, 555-561delTATTCTT, D403N, W488R, M527T), while six correspond to already published mutations (P162A, R109Q, L252P and three C41S). We only focused on those mutations that had been functionally characterized in vitro, and in whom serum TSH was available from family members.

Conclusions: A single grossly mutated allele (such as C41S or 555-561del) invariably leads to a condition of subclinical hypothyroidism, whereas in case of heterozygous carriers of mutations partially affecting the receptor function (such as P162A or L252P), a remarkable variable expressivity was detected among individuals belonging to different generations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child
  • Codon / genetics
  • Congenital Hypothyroidism*
  • Female
  • Gene Expression Regulation / genetics
  • Heterozygote
  • Humans
  • Hypothyroidism / genetics
  • Infant, Newborn
  • Male
  • Models, Genetic
  • Mutation*
  • Pedigree
  • Receptors, Thyrotropin / genetics*
  • Thyrotropin / blood
  • Thyrotropin / genetics*


  • Codon
  • Receptors, Thyrotropin
  • Thyrotropin