A novel mechanism of inherited TBG deficiency: Mutation in a liverspecific enhancer

Alfonso Massimiliano Ferrara, Theodora Pappa, Jiao Fu, Christopher D. Brown, April Peterson, Lars C. Moeller, Kathleen Wyne, Kevin P. White, Anna Pluzhnikov, Vassily Trubetskoy, Marcelo Nobrega, Roy E. Weiss, Alexandra M. Dumitrescu, Samuel Refetoff

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Context: T4-binding globulin (TBG), a protein secreted by the liver, is the main thyroid hormone (TH) transporter in human serum. TBG deficiency is characterized by reduced serum TH levels, but normal free TH and TSH and absent clinical manifestations. The inherited form of TBG deficiency is usually due to a mutation in the TBG gene located on the X-chromosome. Objective: Among the 75 families with X-chromosome-linked TBG deficiency identified in our laboratory, no mutations in the TBG gene were found in four families. The aim of the study was to identify the mechanism of TBG deficiency in these four families using biochemical and genetic studies. Design: Observational cohort, prospective. Setting: University research center. Patients: Four families with inherited TBG deficiency and no mutations in the TBG gene. Intervention: Clinical evaluation, thyroid function tests, and targeted resequencing of 1Mb of the X-chromosome. Results: Next-generation sequencing identified a novelGtoAvariant 20kbdownstreamof theTBG gene in all four families. In silico analysis predicted that the variant resides within a liver-specific enhancer. In vitro studies confirmed the enhancer activity of a 2.2-kb fragment of genomic DNA containing the novel variant and showed that the mutation reduces the activity of this enhancer. The affected subjects share a haplotype of 8 Mb surrounding the mutation, and the most recent common ancestor among the four families was estimated to be 19.5 generations ago (95% confidence intervals, 10.4-37). Conclusions: To our knowledge, the present study is the first report of an inherited endocrine disorder caused by a mutation in an enhancer region.

Original languageEnglish (US)
Pages (from-to)E173-E181
JournalJournal of Clinical Endocrinology and Metabolism
Issue number1
StatePublished - Jan 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


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