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<p>This study defined gene expression changes across different cell types in prefrontal cortex (PFC) of donors with Prader-Willi syndrome (PWS) compared to controls and examined relationships between these changes in blood and PWS symptoms. 8,338 long non-coding RNAs and 17,079 protein-coding genes were examined using single-nucleus RNA-sequencing (snRNA-seq) in the PFC of 8 donors with PWS (4 deletion, 4 non-deletion), and 4 age- and sex-matched neurotypical controls. snRNA-seq analyses showed an increased proportion of interneurons in both PWS groups compared to controls. Fifty-four genes and related pathways were consistently dysregulated across all cell types in the PFC of the PWS group compared to controls, with <i>RPS18</i> being the only protein-coding gene upregulated in PWS PFC across all comparisons. Increase in <i>RPS18</i> mRNA levels in peripheral blood mononuclear cells (PBMCs) of another cohort (16 deletion, 20 non-deletion, ages 1–45 years) assessed using droplet digital PCR was found to be associated with intellectual functioning and challenging behaviors, but not autistic traits in children with PWS due to non-deletion (&lt; 13 years old; <i>N</i> = 19). If confirmed in future studies, these findings may lead to development of prognostic biomarkers and therapeutics targeting consistently dysregulated genes and related pathways between brain and periphery.</p>

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Transcriptomic signatures in brain and blood related to cognitive and psychiatric phenotypes of Prader–Willi syndrome

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月24日

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  • Shokouh Shahrokhi,
  • Emma K. Baker,
  • Michael See,
  • Mirana Ramialison,
  • Dinusha Gamage,
  • Fernando J. Rossello,
  • Helen Heussler,
  • Michael Duhig,
  • Robert D. Nicholls,
  • Anthony J. Hannan,
  • Melissa C. Southey,
  • Olivia Veatch,
  • Waheeda Hossain,
  • Minh Bui,
  • David J. Amor,
  • Merlin G. Butler,
  • David E. Godler

摘要

This study defined gene expression changes across different cell types in prefrontal cortex (PFC) of donors with Prader-Willi syndrome (PWS) compared to controls and examined relationships between these changes in blood and PWS symptoms. 8,338 long non-coding RNAs and 17,079 protein-coding genes were examined using single-nucleus RNA-sequencing (snRNA-seq) in the PFC of 8 donors with PWS (4 deletion, 4 non-deletion), and 4 age- and sex-matched neurotypical controls. snRNA-seq analyses showed an increased proportion of interneurons in both PWS groups compared to controls. Fifty-four genes and related pathways were consistently dysregulated across all cell types in the PFC of the PWS group compared to controls, with RPS18 being the only protein-coding gene upregulated in PWS PFC across all comparisons. Increase in RPS18 mRNA levels in peripheral blood mononuclear cells (PBMCs) of another cohort (16 deletion, 20 non-deletion, ages 1–45 years) assessed using droplet digital PCR was found to be associated with intellectual functioning and challenging behaviors, but not autistic traits in children with PWS due to non-deletion (< 13 years old; N = 19). If confirmed in future studies, these findings may lead to development of prognostic biomarkers and therapeutics targeting consistently dysregulated genes and related pathways between brain and periphery.