Mutations in TBL1X Are Associated With Central Hypothyroidism

Area of Science:

• Endocrinology
• Genetics
• Molecular Biology

Background:

• Congenital central hypothyroidism (CeH) is a rare endocrine disorder affecting thyroid hormone production.
• The genetic causes of isolated CeH are not fully understood, with mutations in TRHR, TSHB, and IGSF1 identified in some cases.

Purpose of the Study:

• To identify mutations in the transducin beta-like protein 1, X-linked (TBL1X) gene in patients with unexplained isolated CeH.
• To investigate the functional consequences of identified TBL1X mutations and their expression in relevant human tissues.

Main Methods:

• Observational study involving clinical and biochemical characterization of patients and relatives.
• Sanger sequencing to identify TBL1X mutations.
• In vitro functional assays and mRNA/protein expression studies in human hypothalamus and pituitary.

Main Results:

• Five novel TBL1X mutations were identified in patients with CeH.
• Mutation carriers showed reduced free T4 (FT4) levels, ranging from low-normal to CeH-diagnostic values.
• Hearing loss was observed in 12 of 19 evaluated mutation carriers.

Conclusions:

• TBL1X gene mutations are a newly identified cause of congenital central hypothyroidism.
• These mutations are associated with both CeH and hearing loss, with variable impacts on FT4 levels.