The role of GLIS3 in thyroid disease as part of a multisystem disorder

Abstract

Congenital hypothyroidism is the most common hereditary endocrine disorder. In a small number of cases, mutations have been identified that are associated with maldevelopment and maldescent of the thyroid. Some of these mutations present as syndromes with a multisystem phenotype such as NKX2-1, PAX8, and FOXE. The association of permanent neonatal diabetes and congenital hypothyroidism was first reported in 2003 and subsequently led to the identification GLIS3 as the mutation responsible for this presentation. GLIS3 is a member of the GLI-similar zinc finger protein family encoding for a nuclear protein with five zinc finger domains and maps to chromosome 9p24. Given the role of GLIS3 in transcriptional activation and repression during embryogenesis, in humans, GLIS3 mutations present with multisystem involvement that also includes renal cystic dysplasia, progressive liver fibrosis and osteopenia. Thyroid findings in GLIS3 patients include thyroid aplasia, diminished colloid with interstitial fibrosis at post-mortem, and apparently normal gross thyroid anatomy on ultrasonography but with temporary TSH resistance on treatment. To date no biological mechanism has explained this variable presentation.

Keywords: GLIS3; hypothyroidism; kidney disease; liver disease; neonatal diabetes.