ESPE Yearbook of Paediatric Endocrinology

J Clin Endocrinol Metab. 2024 Nov 18;109(12):3282-3292. doi: 10.1210/clinem/dgae270. PMID: 38654471

Brief Summary: This study identifies the eukaryotic translation initiation factor EIF4B as a novel candidate gene for congenital hypothyroidism (CH). A de novo EIF4B variant (P328L) was discovered through whole-exome sequencing in 192 CH patients. The authors used patient-derived data, in vitro translation assays, and in vivo zebrafish and mouse models to assess its functional role.

In zebrafish, EIF4B knockdown produced two phenotypic classes. Severely affected embryos exhibited short body length, notochord and tail defects, bradycardia, and reduced eye and ear size, features consistent with hypothyroidism and developmental delay. These embryos showed low thyroid hormone levels, abnormal thyroid morphology, and elevated expression of the thyroid-stimulating hormone subunit βa (TSHBA). T4 supplementation partially rescued heart rate, body length, and TSHBA levels, implicating a thyroid-specific mechanism. However, persistent eye and ear abnormalities suggested additional non-thyroidal effects.

In mice, complete loss of Eif4b caused perinatal lethality, while heterozygous animals appeared phenotypically normal, indicating a dosage-sensitive requirement for EIF4B. Histology confirmed structural thyroid abnormalities in homozygous mutants.

Mechanistically, EIF4B was shown to regulate translation of key thyroid developmental genes. The P328L variant reduced translation efficiency of NKX2-1 and TPO, with a trend toward reduced TG translation, suggesting EIF4B facilitates mRNA translation of essential thyroid genes.

Transcriptomic analysis revealed impaired thyroid cell migration and increased cell adhesion complex formation in the absence of EIF4B, proposing a novel mechanism for thyroid dysgenesis beyond traditional defects in hormone synthesis or migration genes.

In conclusion, this study links translational control and cellular dynamics to thyroid development, expands the genetic landscape of CH, and highlights EIF4B as a diagnostic candidate. It underscores the value of integrating patient genomics with functional modeling to uncover new disease mechanisms in congenital thyroid disease.