Novel Missense Variants in PAX8 and NKX2-1 Cause Congenital Hypothyroidism

Abstract

Primary congenital hypothyroidism (CH) is a common neonatal endocrine disorder characterized by elevated concentrations of thyroid stimulating hormone (TSH) and low concentrations of free thyroxine (FT4). PAX8 and NKX2-1 are important transcription factors involved in thyroid development. In this study, we detected three novel variants in PAX8 (c.149A > C and c.329G > A) and NKX2-1 (c.706A > G) by whole exome sequencing (WES) in three unrelated CH patients with variable phenotypes. The results of Western blot and immunofluorescence analysis showed that the three variants had no effect on protein expression and subcellular localization. However, the results of the electrophoretic mobility shift assay (EMSA) and dual-luciferase reporter assay suggested that the three variants in PAX8 and NKX2-1 both affected their DNA-binding ability and reduced their transactivation capacity. Moreover, a dominant-negative effect in K236E−NKX2-1 was identified by dual-luciferase reporter assay. To sum up, our findings extend our knowledge of the current mutation spectrum of PAX8 and NKX2-1 and provide important information for diagnosing, treating, and preventing CH in these families.

The First Indian Patient With Benign Hereditary Chorea due to a De Novo Mutation in the NKX2-1 Gene

“…6 Our patient had well-controlled hypothyroidism with onset in early childhood and motor delay. This presentation contrasted with that of the patient with the same variant reported by Li et al, 2 who had congenital hypothyroidism and marked motor and language developmental delay. One-third of patients have the typical triad of "brain-lung-thyroid" involvement.…”

“…This study provided functional evidence of the pathogenic nature of this variant. 2 In addition, we also observed a heterozygous variant on chr7:152262989delA (c.1326delA; p.Phe442LeufsTer28) in the KMT2C gene (ENST00000681082) in exon 9. This latter variant was also likely pathogenic (ACMG-PVS1 and PM2) and is known to cause Kleefstra syndrome type 2.…”

“…The combination of brain and thyroid involvement, as in our case, is observed in up to 50% of patients. 1 Thyroid involvement may manifest as congenital hypothyroidism 2 or compensated hypothyroidism in childhood or even adulthood. 6 Our patient had well-controlled hypothyroidism with onset in early childhood and motor delay.…”

Functional identification of two novel variants and a hypomorphic variant in ASS1 from patients with Citrullinemia type I

“…In the c.649_ 651del mutant model, the length of the hydrogen bond between alanine at position 216 and lysine at position 335 was shortened, and a new hydrogen bond between alanine at position 216 and proline at position 213 was formed. In addition, the hydrogen bond between lysine at position 335 and threonine at position 218 was deleted (LI et al, 2023b) . Meanwhile, a change in protein surface charge was predicted in the c.649_651del mutant protein model (Figure 3B).…”