Abstract
Thyroid dysgenesis (TD) accounts for 80% cases of congenital hypothyroidism, which is the most common neonatal disorder. Until now, the gene mutations have been reported associated with TD can only account for 5% cases, suggesting the genetic heterogeneity of the pathology. Nicotinamide nucleotide transhydrogenase (NNT) plays a crucial role in regulating redox homeostasis, patients carrying NNT mutations have been described with a clinical phenotype of hypothyroidism. As TD risk is increased in the context of several syndromes and redox homeostasis is vital for thyroid development and function, NNT might be a candidate gene involved in syndromic TD. Therefore, we performed target sequencing (TS) in 289 TD patients for causative mutations in NNT and conducted functional analysis of the gene mutations. TS and Sanger sequence were used to screen the novel mutations. For functional analysis, we performed western blot, measurement of NADPH/NADPtotal and H2 O2 generation, cell proliferation, and wounding healing assay. As a result, three presumably pathogenic mutations (c.811G > A, p.Ala271Ser; c.2078G > A, p.Arg693His; and c.2581G > A, p.Val861Met) in NNT had been identified. Our results showed the damaging effect of NNT mutations on stability and catalytic activity of proteins and redox balance of cells. In conclusion, our findings provided novel insights into the role of the NNT isotype in thyroid physiopathology and broaden the spectrum of pathogenic genes associated with TD. However, the pathogenic mechanism of NNT in TD is still need to be investigated in further study.