ISSN 1662-4009 (Online)

ESPE Yearbook of Paediatric Endocrinology (2019) 16 3.12 | DOI: 10.1530/ey.16.3.12

TUBB1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology

Stoupa A, Adam F, Kariyawasam D, Strassel C, Gawade S, Szinnai G, Kauskot A, Lasne D, Janke C, Natarajan K, Schmitt A, Bole-Feysot C, Nitschke P, Léger J, Jabot-Hanin F, Tores F, Michel A, Munnich A, Besmond C, Scharfmann R, Lanza F, Borgel D, Poalk M & Carré A



To read the full abstract: EMBO Mol Med 2018;e9569:1–18

TUBB1 encodes a member of the beta-tubulin protein family. Beta-tubulins and alpha-tubulins form dimers, which assemble into microtubules belonging to the intracellular cytoskeleton structure.

The authors identified three different mutations in TUBB1 by whole exome sequencing in a large cohort of patients with congenital hypothyroidism due to thyroid dysgenesis. The thyroid phenotype in the three families ranged from hemiagenesis/hypoplasia to ectopy. The biochemical phenotype was variable even within families, some patients detected by neonatal screening presented with mild to moderate congenital hypothyroidism at confirmatory testing, while some only being diagnosed by systematic familial screening after TUBB1 mutation detection in family members. Interestingly, the patients also showed macrothrombocytes as extrathyroidal pathology, a phenotype previously described for TUBB1 mutations [1]. Extensive functional and developmental studies in mice provided evidence that the three described TUBB1 defects resulted in non-functional alpha/beta tubulin dimers, which could not be assembled to microtubules and ultimately leading to thyroid dysgenesis and macrothrombocytes.

These findings extend the spectrum of proteins involved in normal thyroid development to members of the cytoskeleton and provides evidence for microtubule dysfunction resulting in macrothrombocytes and thyroid dysgenesis. Recently, TUBB1 mutations were also identified in familial thyrombocytopenia, however thyroid function in those cases was not detailed [2]. Thus, further studies are necessary to completely elucidate the role of tubulins in thyroid and platelet development and function.

References: 1. Kunishima S, Kobayashi R, Itoh TJ, Hamaguchi M, Saito H. Mutation of the beta1-tubulin gene associated with congenital macrothrombocytopenia affecting microtubule assembly. Blood 2009;113:458–61.

2. Matsumura T, Nakamura-Ishizu A, Takaoka K, Maki H, Muddineni SSNA, Wang CQ, Suzushima H, Kawakita M, Asou N, Matsuoka M, Kurokawa M, Osato M, Suda T. TUBB1 dysfunction in inherited thyrombocytopenia causes genome instability. Br J Haematol 2019;185;888–902.