Background: Congenital hypothyroidism is primarily due to thyroid dysgenesis (TD). The genes implicated in TD, account for a small number of patients with monogenic forms, less than 5%. Borealin is a major component of the Chromosomal Passenger Complex, an essential regulator of mitosis.
Objective and hypotheses: To understand the role of Borealin mutations found in patients with TD.
Method: We performed whole exome sequencing (WES) in a consanguineous family with TD and subsequently sequenced a cohort of 136 probands with TD. We transfected Nthy ori 3.1 cells and human primary thyrocytes with vectors containing the Borealin-wt or the 3 mutants for functional study. Moreover, we performed transcriptome analysis in the thyroid tissue of a patient with a Borealin mutation.
Results: We identified a homozygous missense mutation p.S148F in the BOREALIN gene (one daughter with ectopic thyroid and the other with hemiagenesis) by WES and two others heterozygous mutations by direct Sanger sequencing: p.R114W (thyroid ectopy) and p.L177W (athyreosis). No effect of the three Borealin mutations was shown on mitosis of Nthy cells. However, we found a significant decrease in migration and in the spreading of Nthy transfected by mutants compared to Nthy-wt. We observed also a decrease expression of a set of genes involved in adhesion of human primary thyrocytes transfected with mutants compared to wt (TLN1, ACTN1, ITGA3, CAV1). These results were well correlated with the same genes expression pattern analyzed in the thyroid tissue of the patient with Borealin-p.R114W.
Conclusion: We identified a new gene, Borealin, involved in the adhesion and the migration of the thyrocytes. Heterozygous as well as homozygous mutations in certain domains of this gene are responsible for thyroid dysgenesis, opening new avenues in the genetics of TD in humans. Supported in part by a PHRC, ClinicalTrials.gov NCT01916018, Sandoz SAS, Merck.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology