Journal
EMBO MOLECULAR MEDICINE
Volume 10, Issue 12, Pages -Publisher
WILEY
DOI: 10.15252/emmm.201809569
Keywords
congenital hypothyroidism; macroplatelets; mutations; thyroid dysgenesis; TUBB1
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Funding
- French public non-profit funding agency Programme Hospitalier de Recherche Clinique [P 110120 - IDRCB 2012-A00797-36]
- EDF
- Sandoz SAS
- Merck Serono France
- non-profit Princess Grace Foundation of Monaco
- SFEDP (Societe Francaise d'Endocrinologie et Diabetologie Pediatrique)
- European Society for Paediatric Endocrinology Research Fellowship Grant
- Alexander S. Onassis Foundation
- FRM fellowship [SPF20140129173]
- program Investissements d'Avenir [ANR-10-LBX-0038, ANR-10-IDEX-0001-02 PSL]
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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 beta-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 alpha/beta-tubulin dimers that cannot be incorporated into microtubules. In mice, Tubb1 knock-out disrupted microtubule integrity by preventing beta 1-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 beta 1-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.
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