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<p>Pontocerebellar hypoplasia (PCH) represents a group of disorders characterized by cerebellum and pons hypoplasia, variable cerebral involvement, microcephaly, severe global developmental delay (GDD), and seizures. We sought the genetic cause of PCH in two siblings. Genetic workup was performed by whole-exome sequencing followed by Sanger validation. Morpholino-knockdown zebrafish embryos with human wild-type gene rescue were used to assess cerebellar development and motor function. Transfected mouse hippocampal cultures and electroporated mouse embryos were employed to assess functional effects on neuronal morphology and development. Both patients presented with profound GDD, severe microcephaly, cataracts, and variably seizures. Their MRIs demonstrated marked cerebellar and pontine hypoplasia. Both were homozygous for a c.416T &gt; C, p.(Leu139Pro) <i>MED29</i> variant which was predicted to be pathogenic. Locomotion and cerebellar GABAergic neurons development were both impaired in <i>MED29</i> Morpholino-knockdown zebrafish and rescued by human wild-type gene expression. ShRNA-knockdown of <i>MED29</i> in mouse hippocampal neurons decreased neurite length and arborization in vitro, and caused defective embryonic neuronal migration in vivo. Overexpression of MED29 p.(Leu139Pro) was consistent with a loss-of-function. Taken together, the Mediator complex regulates transcription processes, and defects in particular subunits are associated with distinct neurodevelopmental phenotypes involving PCH. We conclude that <i>MED29</i> is a novel risk gene for PCH.</p>

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Biallelic MED29 variants cause pontocerebellar hypoplasia with cataracts

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月31日

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  • Leo Arkush,
  • Geeske M. van Woerden,
  • Limor Ziv,
  • Dina Marek-Yagel,
  • Reginald Fonseca,
  • Esmee Brevé,
  • Ortal Barel,
  • Nechama Shalva,
  • Alvit Veber,
  • Yair Anikster,
  • Dominique Ben-Ami Raichman,
  • Banan Musallam,
  • Shai Marcu,
  • Andreea Nissenkorn,
  • Hanna Mandel,
  • Steven A. Kushner,
  • Bruria Ben Zeev,
  • Gali Heimer

摘要

Pontocerebellar hypoplasia (PCH) represents a group of disorders characterized by cerebellum and pons hypoplasia, variable cerebral involvement, microcephaly, severe global developmental delay (GDD), and seizures. We sought the genetic cause of PCH in two siblings. Genetic workup was performed by whole-exome sequencing followed by Sanger validation. Morpholino-knockdown zebrafish embryos with human wild-type gene rescue were used to assess cerebellar development and motor function. Transfected mouse hippocampal cultures and electroporated mouse embryos were employed to assess functional effects on neuronal morphology and development. Both patients presented with profound GDD, severe microcephaly, cataracts, and variably seizures. Their MRIs demonstrated marked cerebellar and pontine hypoplasia. Both were homozygous for a c.416T > C, p.(Leu139Pro) MED29 variant which was predicted to be pathogenic. Locomotion and cerebellar GABAergic neurons development were both impaired in MED29 Morpholino-knockdown zebrafish and rescued by human wild-type gene expression. ShRNA-knockdown of MED29 in mouse hippocampal neurons decreased neurite length and arborization in vitro, and caused defective embryonic neuronal migration in vivo. Overexpression of MED29 p.(Leu139Pro) was consistent with a loss-of-function. Taken together, the Mediator complex regulates transcription processes, and defects in particular subunits are associated with distinct neurodevelopmental phenotypes involving PCH. We conclude that MED29 is a novel risk gene for PCH.