Endocrine Abstracts

Congenital hypothyroidism (CH) is the most common endocrine disorder in neonates, but its etiology is still poorly understood. To identify novel genes, we performed whole exome sequencing in 98 CH patients not harboring known CH candidate genes. Through bioinformatic analysis, eukaryotic translation initiation factor 4B (EIF4B) was identified as the most promising candidate gene. The EIF4B gene was inherited in an autosomal recessive model, and one patient with thyroid dysgenesis carried EIF4B biallelic variants (p.S430F/p.P328L). Functional analysis was performed using morpholino (which is defined as a synthetic oligomer molecule that contains 25 DNA bases on a methylene morpholine backbone) antisense oligomers in zebrafish and CRISPR—Cas9-mediated gene knockout in mice. In zebrafish, the knockdown of eif4ba/b expression caused thyroid dysgenesis and growth retardation. Thyroid hormone levels were significantly decreased in morphants compared with controls. Thyroxine treatment in morphants partially rescued growth retardation. In mice, the homozygous conceptuses of Eif4b+/- parents did not survive. Eif4b knockout embryos showed severe growth retardation, including thyroid dysgenesis and embryonic lethality before E18.5. These experimental data supported a role for EIF4B function in the pathogenesis of the hypothyroid phenotype seen in CH patients. Our work indicated that EIF4B was identified as a novel candidate gene in CH. EIF4B is essential for animal survival, but further studies are needed to validate its role in the pathogenesis of CH.