A novel mutation (p.Lys342Glu) in the thyroid hormone receptor beta gene (THRB) resulting in thyroid hormone resistance

Objectives: Thyroid hormone resistance is a rare inherited syndrome characterized by a reduced response to thyroid hormone. This abnormality may be due to defects in the thyroid hormone receptor beta and several different mutations have been identified. Clinical characteristics include elevated concentrations of free T3 and T4 with inadequately high TSH levels, enlarged thyroid gland and other variable symptoms.

Methods: We identified a 54 year old patient with a history of goiter and subtotal thyroidectomy who presented with elevated fT3, fT4 and TSH levels. Thyroxin administration failed to lower TSH levels and subsequently genetic analysis of the thyroid hormone receptor beta (TR-beta) gene was done. DNA-extraction, PCR amplification and DNA sequencing of exons 7, 8, 9, and 10 were done according to published methods.

Results: A single nucleotid exchange in exon 9, codon 342 (AAA>GAA) was detected, predicting an amino acid exchange (Lysin to Glutamic acid). This so far unpublished mutation is located in the T3 binding region of TR-beta. The Lys>Glu exchange leads to a two charge shift, compatible with a disturbance of ionic interactions in the hormone binding region and thus explaining the loss of function of the affected allele. Since no family members were available for a family study, a group of 100 healthy individuals was analysed. No further carriers of the mutation were detected supporting the pathogenic role of TR-beta (p.Lys342Glu).

Conclusion: In summary we describe a new mutation in the THRB resulting in thyroid hormone resistance. Loss of function may be caused by changed ionic interactions due to the Lys>Glu exchange at codon 342 in the T3 binding region of TR-beta.

Further in vitro expression and binding studies will be required to analyse the functional effects of this mutation.