Isolated TSH deficiency as a cause for congenital hypothyroidism is relatively uncommon. Even more rare is the identification of mutations in the TSHbeta gene, only four of which have been identified. We here report a 4-month-old girl with isolated TSH deficiency born to consanguineous parents. Sequencing of the TSHbeta-subunit gene revealed a homozygous G to A transition at position +5 of the donor splice site of intron 2. TSHbeta gene transcript could not be obtained from fibroblasts or white blood cells by illegitimate amplification. Thus, to investigate further the mechanism leading to TSH deficiency in this patient, we used an in vitro exon-trapping system. The mutation at position +5 of the donor splicing site produced a skip of exon 2. The putative product of translation from a downstream start site is expected to yield a severely truncated peptide of 25 amino acids. Surprisingly, a missense substitution affecting the 14th amino acid of the signal peptide (SigP A14T) was found in one allele of the mother and brother. SigP 14T is polymorphic with a frequency of 1.8% and has no functional consequence.
