Human neuropathology confirms projection neuron and interneuron defects and delayed oligodendrocyte production and maturation in FOXG1 syndrome

Eur J Med Genet. 2021 Sep;64(9):104282. doi: 10.1016/j.ejmg.2021.104282. Epub 2021 Jul 17.

Abstract

The Forkhead transcription factor FOXG1 is a prerequisite for telencephalon development in mammals and is an essential factor controlling expansion of the dorsal telencephalon by promoting neuron and interneuron production. Heterozygous FOXG1 gene mutations cause FOXG1 syndrome characterized by severe intellectual disability, motor delay, dyskinetic movements and epilepsy. Neuroimaging studies in patients disclose constant features including microcephaly, corpus callosum dysgenesis and delayed myelination. Currently, investigative research on the underlying pathophysiology relies on mouse models only and indicates that de-repression of FOXG1 target genes may cause premature neuronal differentiation at the expense of the progenitor pool, patterning and migration defects with impaired formation of cortico-cortical projections. It remains an open question to which extent this recapitulates the neurodevelopmental pathophysiology in FOXG1-haploinsufficient patients. To close this gap, we performed neuropathological analyses in two foetal cases with FOXG1 premature stop codon mutations interrupted during the third trimester of the pregnancy for microcephaly and corpus callosum dysgenesis. In these foetuses, we observed cortical lamination defects and decreased neuronal density mainly affecting layers II, III and V that normally give rise to cortico-cortical and inter-hemispheric axonal projections. GABAergic interneurons were also reduced in number in the cortical plate and persisting germinative zones. Additionally, we observed more numerous PDGFRα-positive oligodendrocyte precursor cells and fewer Olig2-positive pre-oligodendrocytes compared to age-matched control brains, arguing for delayed production and differentiation of oligodendrocyte lineage leading to delayed myelination. These findings provide key insights into the human pathophysiology of FOXG1 syndrome.

Keywords: Delayed myelination; FOXG1 gene; Foetal neuropathology; Interneuron defects; Malformation of cortical development; Microcephaly.

Publication types

  • Case Reports

MeSH terms

  • Aborted Fetus / metabolism
  • Aborted Fetus / pathology
  • Adult
  • Agenesis of Corpus Callosum / genetics*
  • Agenesis of Corpus Callosum / pathology
  • Axons / metabolism
  • Axons / pathology*
  • Brain / embryology
  • Brain / metabolism
  • Brain / pathology
  • Codon, Nonsense
  • Female
  • Forkhead Transcription Factors / genetics*
  • Forkhead Transcription Factors / metabolism
  • GABAergic Neurons / metabolism
  • GABAergic Neurons / pathology
  • Humans
  • Interneurons / metabolism
  • Interneurons / pathology
  • Microcephaly / genetics*
  • Microcephaly / pathology
  • Myelin Sheath / metabolism
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Neurodevelopmental Disorders / genetics*
  • Neurodevelopmental Disorders / pathology
  • Neurogenesis*
  • Oligodendroglia / metabolism
  • Oligodendroglia / pathology*
  • Pedigree
  • Pregnancy
  • Syndrome

Substances

  • Codon, Nonsense
  • FOXG1 protein, human
  • Forkhead Transcription Factors
  • Nerve Tissue Proteins