TUBB 1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology

• DOI: 10.15252/emmm.201809569
• Publication Date: 2018-11-19T10:44:03Z
• Authors: Athanasia Stoupa; Frédéric Adam; Dulanjalee Kariya...; Catherine Strassel; Sanjay Gawade; Gabor Szinnai; Alexandre Kauskot; Dominique Lasne; Carsten Janke; Kathiresan Natarajan; Alain Schmitt; Christine Bole‐Fe...; Patrick Nitschke; Juliane Léger; Fabienne Jabot‐Hanin; Frédéric Tores; Anita Michel; Arnold Munnich; Claude Besmond; Raphaël Scharfmann; François Lanza; Delphine Borgel; Michel Polak; Aurore Carré
• Keywords: Blood Platelets; 0301 basic medicine; Medicine (General); Platelet Aggregation; [SDV]Life Sciences [q-bio]; 610; [SDV.BC]Life Sciences [q-bio]/Cellular Biology; Gene Therapy & Genetic Disease; QH426-470; 576; Mice; 03 medical and health sciences; TUBB1; R5-920; Tubulin; [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB]; [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO]; Genetics; Animals; Humans; thyroid dysgenesis; Research Articles; Mice, Knockout; 0303 health sciences; macroplatelets; TUBB1 Subject Categories Genetics; congenital hypothyroidism; mutations; 3. Good health; Mutation; Thyroid Dysgenesis; Haematology; [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology

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.