Abstract
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.
Highlights
Thyroid dysgenesis (TD) is a feature in 65% of patients with congenital hypothyroidism (CH), the most common neonatal endocrine disorder affecting one in 2,500–3,500 newborns (Deladoey et al, 2011; Barry et al, 2016)
The parents are first cousins (I.1, I.2) with five children including two females [II.1 and II.2] with CH. Both patients were born at full term and diagnosed with CH by routine neonatal screening (Fig 1), which showed thyroid-stimulating hormone (TSH) elevation (164 and 177 lIU/ml in P1 and P2, respectively)
We identified three TUBB1 mutations in patients with thyroid dysgenesis (TD) and macroplatelets
Summary
Thyroid dysgenesis (TD) is a feature in 65% of patients with congenital hypothyroidism (CH), the most common neonatal endocrine disorder affecting one in 2,500–3,500 newborns (Deladoey et al, 2011; Barry et al, 2016). In France, the prevalence of CH due to TD is estimated in 1/5,000 (Barry et al, 2016). TD includes a vast spectrum of developmental thyroid anomalies encompassing athyreosis, thyroid ectopia, hypoplasia of an orthotopic gland, and hemithyroid (Barry et al, 2016; Stoupa et al, 2016). The midline thyroid anlage appears on embryonic day E.8.5 in mice and at 3 gestational weeks (GW) in humans. The midline anlage and ultimobranchial bodies migrate and fuse in the definitive a 2018 The Authors.
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