Background: Congenital central hypothyroidism (CeH) may occur isolated, or in combination with other pituitary hormone deficiencies. Although a third causative gene for CeH was recently reported (IGSF1), the aetiology of isolated CeH has remained unexplained in most cases.
Objective and hypotheses: We hypothesized that in three relatives with unexplained isolated CeH a mutation in another gene might be responsible for the phenotype.
Method: Using X-exome sequencing, we identified a missense mutation in the Transducin β-like protein 1, X-linked (TBL1X) gene. Other pathogenic mutations were excluded with whole exome sequencing. The TBL1X protein is part of the thyroid hormone receptor corepressor complex. Sanger sequencing of this gene in unrelated cases of unexplained isolated CeH revealed five additional missense mutations. We performed clinical and biochemical characterization of the probands and relatives with a mutation identified by family screening. We investigated the functional consequences of the mutations in vitro, and used qPCR and immunostaining to study TBL1X expression in post-mortem human hypothalamus and pituitary tissue.
Results: All probands (n=8, 6 males) had CeH with plasma free thyroxine (FT4) concentrations below the reference interval accompanied by thyrotropin concentrations within the reference interval. Family screening identified mutations in nine females and two males, all with FT4 concentrations in the lower half of the reference interval. Eleven out of 15 evaluated individuals with a mutation had hearing loss. The TBL1X mutations were located in the highly conserved WD40-repeat domain of the protein and influenced its expression and thermal stability, but not the ability to bind other corepressor complex proteins. TBL1X mRNA and protein were expressed in the human hypothalamus (particularly in the paraventricular nucleus) and pituitary.
Conclusion: Mutations in TBL1X are associated with a novel syndrome of familial isolated CeH and hearing loss, presumably resulting from impaired function of the nuclear NCoR/SMRT corepressor complex.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology