Genetics and phenomics of hypothyroidism due to TSH resistance

Luca Persani, Davide Calebiro, Daniela Cordella, Giovanna Weber, Giulia Gelmini, Domenico Libri, Tiziana De Filippis, Marco Bonomi

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

The resistance to thyrotropin (TSH) action is the disease associated with molecular defects hampering the adequate transmission of TSH stimulatory signal into thyroid cells. The defect may in principle affect every step along the cascade of events following the binding of TSH to its receptor (TSHR) on thyroid cell membranes. After the description of the first family affected with loss-of-function (LOF) TSHR mutations in 1995, there is now evidence that TSH resistance is a disease with a broad range of expressivity going from severe congenital hypothyroidism (CH) with thyroid hypoplasia to mild hyperthyrotropinemia (hyperTSH) associated with an apparent euthyroid state. More severe forms occur in patients with disrupting biallelic TSHR mutations and follow a recessive pattern of inheritance. Differential diagnosis in these cases includes the exclusion of other causes of thyroid dysgenesis, such as mutations in thyroid transcription factors. More mild forms may instead occur in patients with monoallelic TSHR defects following a dominant mode of inheritance. In these cases we described the dominant negative effect exerted by some LOF mutants on the activity of the wild-type TSHR. Differential diagnosis involves the exclusion of mild hypothyroidism in autoimmune thyroid disease or pseudohypoparathyroidism associated with genetic or epigenetic defects at the GNAS locus. This review will focus on the prevalence of TSHR mutations, on the molecular mechanisms leading to TSH resistance and on the variable clinical expression of this disease.

Original languageEnglish
Pages (from-to)72-82
Number of pages11
JournalMolecular and Cellular Endocrinology
Volume322
Issue number1-2
DOIs
Publication statusPublished - Jun 2010

Fingerprint

Hypothyroidism
Thyroid Dysgenesis
Defects
Thyroid Gland
Mutation
Differential Diagnosis
Pseudohypoparathyroidism
Congenital Hypothyroidism
Inheritance Patterns
Thyroid Diseases
Thyrotropin
Cell membranes
Epigenomics
Autoimmune Diseases
Transcription Factors
Cell Membrane
Genetics

Keywords

  • CAMP pathway
  • Congenital hypothyroidism
  • Neonatal screening
  • Subclinical hypothyroidism
  • Thyroxine
  • TSH bioactivity
  • TSH receptor
  • TSH resistance

ASJC Scopus subject areas

  • Endocrinology
  • Molecular Biology
  • Biochemistry

Cite this

Genetics and phenomics of hypothyroidism due to TSH resistance. / Persani, Luca; Calebiro, Davide; Cordella, Daniela; Weber, Giovanna; Gelmini, Giulia; Libri, Domenico; De Filippis, Tiziana; Bonomi, Marco.

In: Molecular and Cellular Endocrinology, Vol. 322, No. 1-2, 06.2010, p. 72-82.

Research output: Contribution to journalArticle

Persani, Luca ; Calebiro, Davide ; Cordella, Daniela ; Weber, Giovanna ; Gelmini, Giulia ; Libri, Domenico ; De Filippis, Tiziana ; Bonomi, Marco. / Genetics and phenomics of hypothyroidism due to TSH resistance. In: Molecular and Cellular Endocrinology. 2010 ; Vol. 322, No. 1-2. pp. 72-82.
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