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Objective <p>HSCR is caused by disruption of complex signaling pathways within the gene regulatory network (GRN) during enteric nervous system (ENS) development, including <i>glial cell line-derived neurotrophic factor (GDNF)</i> and <i>GDNF family receptor alpha-1 (GFRα1)</i>. However, pathogenic variants in all GRN genes account for only ~ 80% cases; therefore, the epigenetic role remains to be elucidated. We compared <i>GDNF</i> and <i>GFRα1</i> expression between HSCR patients and controls.</p> Results <p>qPCR revealed an upregulated <i>GDNF</i> expression in both ganglionic (206.37-fold) and aganglionic (126.35-fold) HSCR compared to control colons (ΔC<sub>T</sub> 7.65 ± 2.19 <i>vs</i>. 15.34 ± 1.34; <i>p</i> = 0.0001; and ΔC<sub>T</sub> 8.35 ± 2.57 <i>vs.</i> 15.34 ± 1.34; <i>p</i> = 0.0001). qPCR also showed an upregulated <i>GFRα1</i> expression in both ganglionic (29.66-fold) and aganglionic (18.44-fold) HSCR compared to control colons (ΔC<sub>T</sub> 8.44 ± 1.98 vs. 13.33 ± 1.36; <i>p</i> = 0.0001; and ΔC<sub>T</sub> 9.13 ± 1.46 <i>vs.</i> 13.33 ± 1.36; <i>p</i> = 0.0001). In addition, no significant differences were observed between ganglionic and aganglionic segments for either <i>GDNF</i> or <i>GFRα1</i> (ΔC<sub>T</sub> 7.65 ± 2.19 <i>vs.</i> 8.35 ± 2.57; <i>p</i> = 0.43; and ΔC<sub>T</sub> 8.44 ± 1.98 <i>vs.</i> 9.13 ± 1.46; <i>p</i> = 0.29). Our study demonstrates global aberrant expression of <i>GDNF</i> and <i>GFRα1</i> in HSCR patients. These findings underscore the complexity of HSCR as a multifactorial disorder and highlight the importance of integrated signaling networks in ENS development, providing a rationale for further mechanistic and translational studies.</p>

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Dysregulation of GDNF and GFRα1 expression in multifactorial Hirschsprung disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月19日

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  • Gunadi,
  • Setiani Silvy Nurhidayah,
  • Aleyy Adany,
  • Farah Shahnaz Pravinovia,
  • Siti Maisaroh,
  • Kurnia Corie Tonda,
  • Pramana Adhityo,
  • Estelita Liana,
  • Kristy Iskandar,
  • Andi Dwihantoro

摘要

Objective

HSCR is caused by disruption of complex signaling pathways within the gene regulatory network (GRN) during enteric nervous system (ENS) development, including glial cell line-derived neurotrophic factor (GDNF) and GDNF family receptor alpha-1 (GFRα1). However, pathogenic variants in all GRN genes account for only ~ 80% cases; therefore, the epigenetic role remains to be elucidated. We compared GDNF and GFRα1 expression between HSCR patients and controls.

Results

qPCR revealed an upregulated GDNF expression in both ganglionic (206.37-fold) and aganglionic (126.35-fold) HSCR compared to control colons (ΔCT 7.65 ± 2.19 vs. 15.34 ± 1.34; p = 0.0001; and ΔCT 8.35 ± 2.57 vs. 15.34 ± 1.34; p = 0.0001). qPCR also showed an upregulated GFRα1 expression in both ganglionic (29.66-fold) and aganglionic (18.44-fold) HSCR compared to control colons (ΔCT 8.44 ± 1.98 vs. 13.33 ± 1.36; p = 0.0001; and ΔCT 9.13 ± 1.46 vs. 13.33 ± 1.36; p = 0.0001). In addition, no significant differences were observed between ganglionic and aganglionic segments for either GDNF or GFRα1 (ΔCT 7.65 ± 2.19 vs. 8.35 ± 2.57; p = 0.43; and ΔCT 8.44 ± 1.98 vs. 9.13 ± 1.46; p = 0.29). Our study demonstrates global aberrant expression of GDNF and GFRα1 in HSCR patients. These findings underscore the complexity of HSCR as a multifactorial disorder and highlight the importance of integrated signaling networks in ENS development, providing a rationale for further mechanistic and translational studies.