Very Severe Resistance to Thyroid Hormone β in One of Three Affected Members of a Family with a Novel Mutation in the THRB Gene

Abstract

A 13-year-old female with a novel THRB gene mutation (c.1033G>T, p.G345C) presented with 3- to 6-fold higher serum iodothyronine levels and more severe clinical manifestation than 2 other family members carrying the same mutation. The leukocytes of the proband expressed both wild-type and mutant THRB mRNAs, excluding the possibility of a partial deletion of the allele not carrying the mutation. The proband's fibroblasts showed reduced responsiveness to triiodothyronine compared with those of another affected family member. The more severe clinical and biochemical phenotype suggest a modifier-mediated worsening of the resistance to thyroid hormone.

Keywords: cofactor; mutation; non-TR-RTH; resistance to thyroid hormone; thyroid hormone receptor.

FIG. 1.

(A) Pedigree of the family indicating the genotype of each individual and the results of thyroid function tests, aligned with the symbol representing each family member. (B) Results of THRB locus haplotyping show that the proband and brother inherited the same maternal allele. (C) Sequence of cDNA derived from white blood cells mRNA of the proband, covering the region of the THRB mutation. The location of the primers used in the cDNA amplification is indicated. (D, E) TH responsiveness of the subjects' skin fibroblasts. After culture for 48 hours in medium depleted of TH, fibroblasts were treated with three different amounts of T3, 0.5, 2, and 5 nM, for additional 24 hours. The relative amount of mRNAs, compared with that in fibroblasts cultured in the absence of T3, is given as percentage increase. TH, thyroid hormone; T3, triiodothyronine.