<scp>TUBB</scp> 1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology

The genetic causes of congenital hypothyroidism due to thyroid dysgenesis (TD) remain largely unknown. We identified three novel <i>TUBB1</i> gene mutations that co-segregated with TD in three distinct families leading to 1.1% of <i>TUBB1</i> mutations in TD study cohort. <i>TUBB1</i> (Tubulin, Beta 1 Class VI) encodes for a member of the β-tubulin protein family. <i>TUBB1</i> gene is expressed in the developing and adult thyroid in humans and mice. All three <i>TUBB1</i> mutations lead to non-functional α/β-tubulin dimers that cannot be incorporated into microtubules. In mice, <i>Tubb1</i> knock-out disrupted microtubule integrity by preventing β1-tubulin incorporation and impaired thyroid migration and thyroid hormone secretion. In addition, <i>TUBB1</i> 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.