Niedobór białka SYNGAP1 zaburza wczesny rozwój mózgu i przyspiesza dojrzewanie neuronów w modelach pochodzących od pacjentów
SYNGAP1 haploinsufficiency disrupts early neurodevelopment and accelerates intrinsic neuronal maturation in human patient-derived models
W skrócie
[Preprint - wstępne wyniki] Badacze wykorzystali komórki macierzyste pacjentów do studiowania rzadkiej choroby neurologicznej zwanej epilepsją rozwojową SYNGAP1, która powoduje upośledzenie intelektualne i trudne do leczenia napady. Odkryli, że brak połowy białka SYNGAP1 zaburza bardzo wczesne etapy rozwoju mózgu, powodując nieprawidłowe ukształtowanie jego struktur oraz przyspieszając dojrzewanie komórek nerwowych. Te nowe ustalenia sugerują, że problemy przy SYNGAP1 zaczynają się już przed powstaniem połączeń między neuronami, a nie tylko w nich.
Oryginalny abstract (angielski)
SYNGAP1 developmental and epileptic encephalopathy (DEE) is a severe neurodevelopmental disorder characterised by intellectual disability, developmental delay, and refractory epilepsy caused by heterozygous variants in SYNGAP1, which encodes Synaptic Ras GTPase-activating protein 1. While SYNGAP1 is best known for its role at the postsynaptic density, increasing evidence indicates that haploinsufficiency also disrupts early neurodevelopment. Here, we used patient-derived induced pluripotent stem cell (iPSC) models to investigate early neurodevelopmental and neuronal phenotypes associated with SYNGAP1 haploinsufficiency. iPSCs derived from a female patient carrying the frameshift variant p.Leu150Valfs*6 were differentiated into two complementary models: micropatterned neural rosettes representing early neuroepithelial organisation and NGN2-induced excitatory neurons representing postmitotic functional development. Patient-derived neural rosettes displayed enlarged, dysmorphic lumens, indicating disrupted neuroepithelial organisation at the earliest stages of brain development. Transcriptomic profiling revealed widespread dysregulation of genes involved in neurodevelopment, cell adhesion and ion channel regulation, including coordinated downregulation of protocadherin family members. Whole-cell patch-clamp electrophysiology demonstrated reduced input resistance, larger action potential amplitudes, and increased inward and outward current densities, consistent with accelerated intrinsic neuronal maturation rather than generalized hyperexcitability. Together, these complementary findings demonstrate that SYNGAP1 haploinsufficiency disrupts early human brain development and accelerates intrinsic neuronal maturation, with pathogenic mechanisms emerging before synaptogenesis and extending beyond SYNGAP1's established synaptic role.