PUBLICATION
Biallelic MED29 variants cause pontocerebellar hypoplasia with cataracts
- Authors
- Arkush, L., van Woerden, G.M., Ziv, L., Marek-Yagel, D., Fonseca, R., Brevé, E., Barel, O., Shalva, N., Veber, A., Anikster, Y., Ben-Ami Raichman, D., Musallam, B., Marcu, S., Nissenkorn, A., Mandel, H., Kushner, S.A., Ben Zeev, B., Heimer, G.
- ID
- ZDB-PUB-250801-8
- Date
- 2025
- Source
- European journal of human genetics : EJHG : (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Female
- Mediator Complex*/genetics
- Mediator Complex*/metabolism
- Mice
- Zebrafish/genetics
- Animals
- Male
- Cataract*/genetics
- Cataract*/pathology
- Cerebellar Diseases*/genetics
- Cerebellar Diseases*/pathology
- Humans
- PubMed
- 40745490 Full text @ Eur. J. Hum. Genet.
Citation
Arkush, L., van Woerden, G.M., Ziv, L., Marek-Yagel, D., Fonseca, R., Brevé, E., Barel, O., Shalva, N., Veber, A., Anikster, Y., Ben-Ami Raichman, D., Musallam, B., Marcu, S., Nissenkorn, A., Mandel, H., Kushner, S.A., Ben Zeev, B., Heimer, G. (2025) Biallelic MED29 variants cause pontocerebellar hypoplasia with cataracts. European journal of human genetics : EJHG. :.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping