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Nicotinamide nucleotide transhydrogenase mutation analysis in Chinese patients with thyroid dysgenesis
Miaomiao Li1, Weibing Tian2, Fengqi Wang1
1The Affiliated Hospital of Qingdao University, Medical Genetic Department, Prenatal Diagnosis Center, Qingdao, China.
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.
Insights
Mutations in the Nicotinamide nucleotide transhydrogenase (NNT) gene are linked to thyroid dysgenesis (TD), a common cause of congenital hypothyroidism. This study identified three new NNT mutations, highlighting NNT
Area of Science:
- Endocrinology and Genetics
- Molecular Biology and Cellular Physiology
Background:
- Thyroid dysgenesis (TD) is the primary cause of congenital hypothyroidism, a prevalent neonatal disorder, accounting for 80% of cases.
- Current genetic explanations for TD are limited, identifying causative mutations in only 5% of patients, indicating significant genetic heterogeneity.
- Nicotinamide nucleotide transhydrogenase (NNT) is crucial for redox homeostasis, and its mutations are associated with hypothyroidism, suggesting a potential role in syndromic TD.
Purpose of the Study:
- To investigate the involvement of the Nicotinamide nucleotide transhydrogenase (NNT) gene in syndromic thyroid dysgenesis (TD).
- To identify novel causative mutations in the NNT gene within a cohort of TD patients.
- To functionally characterize the identified NNT mutations and assess their impact on cellular redox balance and thyroid function.
Main Methods:
- Target sequencing (TS) and Sanger sequencing were employed to screen for NNT gene mutations in 289 TD patients.
- Functional analyses included western blotting, measurement of NADPH/NADP(total) and H2O2 levels, cell proliferation assays, and wound healing assays.
- These methods were used to evaluate the effects of identified NNT mutations on protein stability, enzyme activity, and cellular redox state.
Main Results:
- Three potentially pathogenic mutations in the NNT gene (c.811G>A, p.Ala271Ser; c.2078G>A, p.Arg693His; and c.2581G>A, p.Val861Met) were identified in TD patients.
- The identified NNT mutations demonstrated detrimental effects on protein stability and catalytic activity.
- Functional assays revealed that these mutations disrupt the cellular redox balance, impacting key cellular processes.
Conclusions:
- The study identifies NNT as a novel candidate gene implicated in the pathophysiology of thyroid dysgenesis.
- The findings expand the spectrum of known genetic factors contributing to TD and congenital hypothyroidism.
- Further research is warranted to elucidate the precise pathogenic mechanisms through which NNT mutations contribute to TD.
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