Background: Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder, with an incidence of 1:3000 neonates, and one of the most frequent preventable causes of mental retardation worldwide. Most (65%) cases of primary permanent CH are due to thyroid dysgenesis (TD). However, a genetic cause is identified in less than 5% of CH due to DT.
Methods: We performed WES (Whole Exome Sequencing) for siblings with childhood-onset TD and we analyzed 270 TD cases by targeted NGS.
Results: We identified three novel TUBB1gene mutations that co-segregated with TD in three affected families. TUBB1(Tubulin, Beta 1 Class VI) encodes a member of the ß-tubulin protein family. TUBB1 gene is expressed in the developing and adult thyroid in humans and mice. All three TUBB1 mutations lead to nonfunctional α/ß-tubulin dimers that cannot be incorporated into microtubules. First, in Tubb1knock-out(−/−)mice, we observed in vivo impaired thyroid proliferation and migration during development. Second, final thyroid differentiation was abnormal in Tubb1−/−embryos, with increased T4 within the thyroid follicular cells, probably reflecting impaired hormone secretion. Third, at 3 months of age, serum TSH levels were higher and T4 levels lower in Tubb1−/− in comparison with wild-type mice, suggesting hypothyroidism in the mutants. Moreover, thyrocytes ultrastructure examined by electron microscopy showed larger numbers of dense vesicles in Tubb1−/−versus wild-type thyrocytes suggesting impaired hormone secretion. In addition, TUBB1 mutations in patients caused macroplatelets observed in blood smears with high mean platelet volume in complete blood counts and hyperaggregation of human platelets.
Conclusions: Our data highlight unexpected roles for ß1-tubulin, via the microtubules, in thyroid development and function and in platelet physiology. Special concerns should be raised for the CH patients bearing TUBB1mutation, as they may have an increased risk for thrombosis in adult life. Finally, these findings expand the spectrum of the rare pediatric diseases related to tubulin mutations and provide new insights into the genetic background and mechanisms involved in congenital hypothyroidism and thyroid dysgenesis.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology