This is a mechanism module, not a specific disease entry. Disorder entries reference individual nodes via conforms_to (for example, "pial_basement_membrane_radial_glial_endfoot_failure#Pial Basement Membrane Breach"). Use this module for cobblestone-like or bilateral frontoparietal polymicrogyria mechanisms when the shared pathograph is pial basement membrane/radial-glial basal endfoot failure followed by neuronal overmigration. Do not use it for primary microtubule-dependent neuronal migration arrest, apical neuroependyma/periventricular heterotopia, Reelin terminal translocation defects, or broad PI3K-AKT-mTOR cortical overgrowth unless a disease-specific branch independently shows this pial-boundary skeleton.
Pial Boundary-Failure Overmigration Model
pial_boundary_overmigration_model
CANONICAL
Evidence: 2
Evidence balance
2 support
Pathogenic disruption of the pial ECM interface, especially through alpha-dystroglycan O-mannosylation or GPR56-COL3A1 signaling, weakens basement membrane integrity and radial-glial basal endfoot anchoring. The causal readout is not primarily slow or failed neuronal locomotion; it is loss of the cortical pial boundary that allows overmigration and ectopic extracortical/cobblestone-like tissue.
Which aspects of pial basement membrane and radial-glial basal endfoot failure in mouse or other models faithfully map to human cobblestone-like cortical malformations, PMG overlap, epilepsy risk, and regional gyral patterning?
HUMAN MODEL MISMATCH
OPEN
gap_pial_boundary_human_model_translatability
Attached to:
Pial Basement Membrane Breach
Radial-Glial Basal Endfoot Detachment
Neuronal Overmigration Across the Pial Boundary
The review and primary papers support a coherent boundary-failure mechanism, but several translatability gaps remain: FKRP mouse knock-in versus knock-down severity differs from patients, human GPR56 regulation is shaped by gyrencephalic/regional enhancers, PMG mechanisms remain incompletely resolved, and seizures are common in human MCDs while often absent from animal models. This is a human/model mismatch knowledge gap rather than a generic missing-mechanism gap.
Proposed experiments:
Human cortical organoid pial-ECM and radial-glial endfoot perturbation panel
Alpha-Dystroglycan Glycosylation and ECM Ligand Binding Failure
trigger
Pathogenic variants in DAG1 or in dystroglycan O-mannosylation pathway genes reduce functional alpha-dystroglycan glycosylation and impair binding to extracellular matrix ligands such as laminin. Representative upstream genes include POMT1, POMT2, POMGNT1, FKTN, FKRP, LARGE1, CRPPA (the current symbol for ISPD), POMK, B4GAT1, and B3GALNT2.
Downstream
-
Pial Basement Membrane Assembly Failure
GPR56-COL3A1 Pial ECM Signaling Failure
trigger
Pathogenic ADGRG1/GPR56 or COL3A1 variants impair a pial ECM receptor-ligand axis required for regional cortical development, pial basement membrane integrity, and inhibition of inappropriate neuronal migration beyond the pial surface.
Downstream
-
Pial Basement Membrane Breach
Pial Basement Membrane Assembly Failure
central effector
Reduced dystroglycan-laminin binding weakens assembly and maintenance of basement membrane components at the pial surface. This node captures the ECM-assembly branch that feeds into pial basal lamina discontinuity.
Downstream
-
Pial Basement Membrane Breach
Pial Basement Membrane Breach
central effector
Failure of basement membrane assembly or GPR56-COL3A1 signaling produces discontinuities and breaches in the pial basal lamina/glia limitans. This is the central boundary defect that permits downstream overmigration.
Downstream
-
Radial-Glial Basal Endfoot Detachment
-
Cajal-Retzius Cell Mislocalization
Cajal-Retzius Cell Mislocalization
amplifier
Boundary failure disrupts marginal-zone organization and mislocalizes Cajal-Retzius cells, which can amplify cortical disorganization and severity across dystroglycanopathy models.
Downstream
-
Neuronal Overmigration Across the Pial Boundary
Neuronal Overmigration Across the Pial Boundary
effector
With the pial boundary breached and radial-glial endfeet detached, neurons can migrate beyond the cortical surface rather than stopping within the cortical plate/marginal zone. This overmigration is the key mechanistic output that distinguishes this module from intrinsic neuronal migration arrest modules.
Downstream
-
Cobblestone-Like Cortical Malformation and PMG Overlap