TUBB1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology

Whole ‐exome sequencing in a consanguineous family with Congenital Hypothyroidism (CH) revealed a novel homozygous mutation inTUBB1, encoding for a member of beta ‐tubulins, essential for microtubule organisation. Until now,TUBB1 mutations were only known to be involved in platelet disorders. AbstractThe genetic causes of congenital hypothyroidism due to thyroid dysgenesis (TD) remain largely unknown. We identified three novelTUBB1 gene mutations that co ‐segregated with TD in three distinct families leading to 1.1% ofTUBB1 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 threeTUBB1 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 hypothyroidi...

Source: EMBO Molecular Medicine - November 19, 2018 Category: Molecular Biology Authors: Athanasia Stoupa, Fr édéric Adam, Dulanjalee Kariyawasam, Catherine Strassel, Sanjay Gawade, Gabor Szinnai, Alexandre Kauskot, Dominique Lasne, Carsten Janke, Kathiresan Natarajan, Alain Schmitt, Christine Bole‐Feysot, Patrick Nitschke, J Tags: Research Article Source Type: research