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The W546X Mutation of the Thyrotropin Receptor Gene: Potential Major Contributor to Thyroid Dysfunction in a Caucasian Population

Departments of Medicine (N.J., M.L.), Medical Biochemistry (N.J., C.E.), Psychological Medicine (N.W., M.O.), and Child Health (J.W.G.), University of Wales College of Medicine, Cardiff CF4 4XN, United Kingdom

Address all correspondence and requests for reprints to: Dr. Marian Ludgate, Department of Medicine, Endocrinology, Metabolism and Diabetes Section, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom. E-mail: ludgate{at}cf.ac.uk.

Congenital hypothyroidism (CH) occurs in approximately 1 in 3000 births and can be caused by mutations in 9 known genes, including that encoding the TSH receptor (TSHR).

We report on two Welsh siblings, detected by neonatal screening, who had normal sized and placed glands but negative isotope uptake. Genomic DNA was obtained from both siblings and parents, the TSHR amplified using pairs of intronic and/or overlapping exonic primers and the PCR products sequenced automatically. Both siblings were homozygous for a previously described G to A transition producing a missense mutation, W546X, in the fourth membrane spanning region of the TSHR, rendering it unresponsive to TSH. Both parents were heterozygous and unrelated; furthermore, the W546X has been described in three further families (one of which is Welsh), suggesting that it may be a relatively common mutation.

We genotyped 368 euthyroid Welsh individuals using single nucleotide primer extension, and found 366 homozygous wild-type (G:G) and 2 heterozygous (G:A) for the mutation.

In conclusion, CH in the siblings is due to the missense mutation, W546X, in their TSHR gene. The W546X allele was detected in approximately 1 in 180 individuals and may be a major contributor to hypothyroidism in the Welsh population.

This work was supported by grants from the Wales Office of Research and Development and the UK Medical Research Council.

Abbreviations: CH, Congenital hypothyroidism; NSIS, sodium/iodide symporter; SH, subclinical hypothyroidism; TBAB, thyroid-blocking antibodies; TG, thyroglobulin; TTF 1 and TTF2, thyroid transcription factors 1 and 2; TPO, thyroperoxidase; TSHR, TSH receptor.

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