TUBB 1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology

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.

Molecular defects in thyroid dysgenesis

“…In a recent paper Stoupa et al identified three different TUBB1 mutations strongly associated to TD. 45 Within the same family, two patients presented thyroid gland ectopia and macroplatelets, phenotype associated to a homozygous TUBB1 loss-of-function mutation.…”

“…In order to find the role of TUBB1 gene mutations found in TD patients, the null mouse model was recently generated . TUBB1 encodes for tubulin beta 1, class VI, a protein of the β‐tubulin family, which is incorporated into microtubules as α/β dimers.…”

“…Within the same family, two patients presented thyroid gland ectopia and macroplatelets, phenotype associated to a homozygous TUBB1 loss‐of‐function mutation. Moreover, in a cohort of 270 TD patients, they demonstrated that 1.1% of subjects possessed a loss‐of‐function mutation in TUBB1 associated to a variable thyroid phenotype ranging from gland ectopia to mild thyroid asymmetry, thyroid hypoplasia and hemithyroid . The variability of the phenotype, even within the same familial cluster, could be explained the hypothesis of random autosomal monoallelic gene expression in the thyroid, that is, the transcription of a gene from one of two homologous alleles …”

“…Moreover, in a cohort of 270 TD patients, they demonstrated that 1.1% of subjects possessed a loss-of-function mutation in TUBB1 associated to a variable thyroid phenotype ranging from gland ectopia to mild thyroid asymmetry, thyroid hypoplasia and hemithyroid. 45 The variability of the phenotype, even within the same familial cluster, could be explained the hypothesis of random autosomal monoallelic gene expression in the thyroid, that is, the transcription of a gene from one of two homologous alleles. 6,63,64 27,67,68 Moreover, other syndromic forms involving thyroid abnormalities exist, in which the underling genetic alteration is still missing.…”

Identification of <b><i>Transient Receptor Potential Channel 4-Associated Protein</i></b> as a Novel Candidate Gene Causing Congenital Primary Hypothyroidism

“…Abnormalities in thyroid development at any step such as differentiation, cell migration, fusion, and survival can lead to TD. So far, 10 genes with various clinical spectra have been identified in sporadic and familial TD: PAX8, NKX2-1, FOXE1, probably NKX2-5, TSHR, GLIS3, NTN1, JAG1, CDCA8, and TUBB1 [4][5][6]. However, these mutations are detected in only 5% of patients with CH.…”