INSERM U1016, Faculté de Médecine, Cochin Institute, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
IMAGINE Institute Affiliate, Paris, France.
EMBO Mol Med. 2018 Dec;10(12). doi: 10.15252/emmm.201809569.
The genetic causes of congenital hypothyroidism due to thyroid dysgenesis (TD) remain largely unknown. We identified three novel gene mutations that co-segregated with TD in three distinct families leading to 1.1% of mutations in TD study cohort. (Tubulin, Beta 1 Class VI) encodes for a member of the β-tubulin protein family. gene is expressed in the developing and adult thyroid in humans and mice. All three mutations lead to non-functional α/β-tubulin dimers that cannot be incorporated into microtubules. In mice, knock-out disrupted microtubule integrity by preventing β1-tubulin incorporation and impaired thyroid migration and thyroid hormone secretion. In addition, 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.
由于甲状腺发育不全导致的先天性甲状腺功能减退症（TD）的遗传原因在很大程度上仍然未知。我们在三个不同的家族中发现了三个新的基因突变，这些突变与 TD 共分离，导致 TD 研究队列中的突变率为 1.1%。β-微管蛋白 1 类 VI（Tubulin, Beta 1 Class VI）编码β-微管蛋白家族的一个成员。在人和小鼠中， 基因在甲状腺的发育和成年期表达。这三种 突变导致无功能的α/β-微管二聚体，无法掺入微管。在小鼠中， 敲除通过阻止β1-微管蛋白掺入而破坏微管完整性，并损害甲状腺迁移和甲状腺激素分泌。此外， 突变导致巨血小板的形成和人类血小板在低剂量激动剂刺激后的过度聚集。我们的数据突出了β1-微管在甲状腺发育和血小板生理学中的意外作用。最后，这些发现扩展了与微管编码基因突变相关的罕见儿科疾病的范围，并为先天性甲状腺功能减退症和甲状腺发育不全涉及的遗传背景和机制提供了新的见解。
