HPDL Gene Mutations Linked to Progressive Neurological Disorder Through Disruption of Brain Cell Development
Researchers using patient-derived stem cell cultures found that mutations in the HPDL gene cause progressive synaptic failure, loss of support cells, and neuronal death in developing human cortex. The study used long-term iPSC-derived cortical cultures from four patients to track how HPDL deficiency unfolds over time. The findings help explain how an early developmental disruption leads to later, progressive neurodegeneration in children carrying these mutations.
A new preprint study published on bioRxiv investigated how biallelic pathological variants in the HPDL gene cause severe childhood neurological disease by modeling the condition in human iPSC-derived cortical cultures from four affected patients. The researchers found that HPDL-deficient cultures exhibit progressive loss of postsynaptic structures (PSD95-positive puncta), indicating synaptic deterioration, even as general neuronal maturation markers remained largely intact. Alongside synaptic decline, the cultures showed a marked reduction in astrocytes and oligodendrocytes—glial cells critical for neuronal support—as well as increased neuronal apoptosis. Transcriptomic analysis revealed dysregulation of genes involved in extracellular matrix organization, cellular stress, and neurodegeneration. Unexpectedly, late-stage mutant cultures also showed reactivation of early developmental gene programs, including aberrant expression of the proneural regulator NEUROD4, suggesting that cell identity becomes unstable during cortical maturation. The authors propose a two-phase model in which HPDL deficiency first disrupts the timing of cortical development and then drives a collapse of the neuro-glial unit, connecting premature neurogenesis to synaptic failure and progressive degeneration.
What's missing
The study is a preprint and has not yet undergone peer review. The model relies on in vitro iPSC-derived cultures, which may not fully recapitulate in vivo human cortical development or disease progression. The sample size is limited to four patients. It remains unclear whether the observed transcriptional and cellular changes translate directly to therapeutic targets or disease biomarkers in living patients.
What different sources said
- bioRxivCenter
Pathological variants in HPDL cause collapse of the neuro-glial unit during human cortical maturation
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