Journal Article

TUBB1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology

Gawade, Sanjay, Lasne, Dominique, Jabot‐Hanin, Fabienne, Tores, Frédéric, Kauskot, Alexandre, Léger, Juliane, Strassel, Catherine, Janke, Carsten, Polak, Michel, Natarajan, Kathiresan, Michel, Anita, Schmitt, Alain, Besmond, Claude, Scharfmann, Raphaël, Lanza, François, Nitschke, Patrick, Adam, Frédéric, Bole‐Feysot, Christine, Carré, Aurore, Kariyawasam, Dulanjalee, Szinnai, Gabor, Munnich, Arnold, Stoupa, Athanasia, Borgel, Delphine

2018

Overview

The genetic causes of congenital hypothyroidism due to thyroid dysgenesis (TD) remain largely unknown. We identified three novel TUBB1 gene mutations that co‐segregated with TD in three distinct families leading to 1.1% of TUBB1 mutations in TD study cohort. TUBB1 (Tubulin, Beta 1 Class VI) encodes for a member of the β‐tubulin protein family. TUBB1 gene is expressed in the developing and adult thyroid in humans and mice. All three TUBB1 mutations lead to non‐functional α/β‐tubulin dimers that cannot be incorporated into microtubules. In mice, Tubb1 knock‐out disrupted microtubule integrity by preventing β1‐tubulin incorporation and impaired thyroid migration and thyroid hormone secretion. In addition, TUBB1 mutations caused the formation of macroplatelets and hyperaggregation of human platelets after stimulation by low doses of agonists. Our data highlight unexpected roles for β1‐tubulin in thyroid development and in platelet physiology. Finally, these findings expand the spectrum of the rare paediatric diseases related to mutations in tubulin‐coding genes and provide new insights into the genetic background and mechanisms involved in congenital hypothyroidism and thyroid dysgenesis. Synopsis Whole‐exome sequencing in a consanguineous family with congenital hypothyroidism (CH) revealed a novel homozygous mutation in TUBB1 , encoding for a member of beta‐tubulins, essential for microtubule organisation. Until now, TUBB1 mutations were only known to be involved in platelet disorders. Two more mutations were identified in two distinct families with thyroid dysgenesis (TD) and abnormal platelet physiology, reinforcing the link between TUBB1 mutations and thyroid disease. TUBB1 is expressed in the developing and adult thyroid in humans and mice. Tubb1 −/− mice have large platelets and show hypothyroidism with early thyroid progenitors proliferation defects, altered thyroid migration and failure of thyroid hormone synthesis. Platelet findings concerned basal activation and increased aggregation. These results expand our knowledge on genetic background of CH and TD. Graphical Abstract Whole‐exome sequencing in a consanguineous family with Congenital Hypothyroidism (CH) revealed a novel homozygous mutation in TUBB1 , encoding for a member of beta‐tubulins, essential for microtubule organisation. Until now, TUBB1 mutations were only known to be involved in platelet disorders.

• Publisher: Nature Publishing Group UK,Wiley Open Access,John Wiley and Sons Inc,Springer Nature
• Subject: Cell Behavior / Cellular Biology / congenital hypothyroidism / EMBO16 / EMBO18 / Human health and pathology / Life Sciences / macroplatelets / mutations / Research Article / thyroid dysgenesis / Tissues and Organs / TUBB1