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Congenital Secondary Hypothyroidism Caused by Exon Skipping due to a Homozygous Donor Splice Site Mutation in the TSHß-Subunit Gene

Children’s Hospital of the Johannes Gutenberg University of Mainz (J.P., R.M., D.P.) and Städtisches Krankenhaus Hagen (U.A., G.K.), D-55101 Mainz, Germany; and Departments of Medicine and Pediatrics, J. P. Kennedy, Jr., Mental Retardation Research Center (S.R.), and Committee on Genetics (S.R., A.D.), University of Chicago, Chicago, Illinois 60637-1470

Address all correspondence and requests for reprints to: Samuel Refetoff, M.D., Thyroid Study Unit, Departments of Medicine and Pediatrics, University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois 60637. E-mail: refetoff{at}medicine.bsd.uchicago.edu

Isolated TSH deficiency as a cause for congenital hypothyroidism is relatively uncommon. Even more rare is the identification of mutations in the TSHß 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 TSHß-subunit gene revealed a homozygous G to A transition at position +5 of the donor splice site of intron 2. TSHß 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.

This work was supported in part by NIH Grants DK-15070, and RR-00055 and the Tivoli Wien Katz fund.

¹ Numbering begins with the first amino acid of the mature protein, thus excluding the signal peptide (SigP).

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