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Purpose <p>Congenital isolated adrenocorticotropic hormone deficiency (CIAD) is an autosomal recessive disorder. This study identifies novel <i>TBX19</i> variants for CIAD patients, explores its possible effect mechanism at the structural, functional and protein levels, and guides clinicians better understand the condition.</p> Methods <p>The clinical characteristics of three CIAD children were summarized. Multiple sequence alignment was performed and five algorithms, PROVEA, PolyPhen2, Mutation Taster, FATHMM, and I Mutant2.0, were used for the pathogenicity prediction. In addition, the three-dimensional protein structure of wild-type <i>TBX19</i> was generated by Alphafold 3 and its variants were shown using PyMOL. Furthermore, immunoblotting analysis was applied to examine changes in the protein levels and the luciferase reporter assay was performed to further investigate the effects of <i>TBX19</i> and its variants on pro-opiomelanocortin (<i>POMC</i>) transcriptional activity.</p> Results <p>We describe three Chinese patients with CIAD caused by <i>TBX19</i> variants. The <i>TBX19</i> variant, c.856C&gt;T (p.R286*) was classified as pathogenic according to ACMG, whereas the other four variants, c.377C&gt;T (p.P126L), c.602A&gt;T (p.E201V), c.401A&gt;G (p.H134R) and c.299G&gt;A (p.R100H) were predicted to be disease-causing. Variants lead to alter interactions, conformational changes in proteins or truncate protein. <i>TBX19</i> and <i>PITX1</i> cooperated, resulting in a strong synergistic activation effect on <i>POMC</i> transcriptional expression. A functional study showed that the variants in our study result in a significant suppression of <i>POMC</i> transcriptional activity compared to wild-type <i>TBX19</i>.</p> Conclusions <p>Our study identifies five <i>TBX19</i> loss-of-function variants, two of which are novel and that provides new perspectives into the pathophysiological mechanism and expands the variant spectrum in IAD.</p>

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Functional study of three cases with novel TBX19 variants

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月8日

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  • NokI Lei,
  • Xiang Qiu,
  • Wunying Li,
  • Yanlin Liu,
  • Ronggui Hu,
  • Chuanyin Li,
  • Wenli Lu

摘要

Purpose

Congenital isolated adrenocorticotropic hormone deficiency (CIAD) is an autosomal recessive disorder. This study identifies novel TBX19 variants for CIAD patients, explores its possible effect mechanism at the structural, functional and protein levels, and guides clinicians better understand the condition.

Methods

The clinical characteristics of three CIAD children were summarized. Multiple sequence alignment was performed and five algorithms, PROVEA, PolyPhen2, Mutation Taster, FATHMM, and I Mutant2.0, were used for the pathogenicity prediction. In addition, the three-dimensional protein structure of wild-type TBX19 was generated by Alphafold 3 and its variants were shown using PyMOL. Furthermore, immunoblotting analysis was applied to examine changes in the protein levels and the luciferase reporter assay was performed to further investigate the effects of TBX19 and its variants on pro-opiomelanocortin (POMC) transcriptional activity.

Results

We describe three Chinese patients with CIAD caused by TBX19 variants. The TBX19 variant, c.856C>T (p.R286*) was classified as pathogenic according to ACMG, whereas the other four variants, c.377C>T (p.P126L), c.602A>T (p.E201V), c.401A>G (p.H134R) and c.299G>A (p.R100H) were predicted to be disease-causing. Variants lead to alter interactions, conformational changes in proteins or truncate protein. TBX19 and PITX1 cooperated, resulting in a strong synergistic activation effect on POMC transcriptional expression. A functional study showed that the variants in our study result in a significant suppression of POMC transcriptional activity compared to wild-type TBX19.

Conclusions

Our study identifies five TBX19 loss-of-function variants, two of which are novel and that provides new perspectives into the pathophysiological mechanism and expands the variant spectrum in IAD.