SRPX2-related speech-epilepsy-polymicrogyria is an X-linked neurodevelopmental disorder boundary in which reported SRPX2 variants affect rolandic/sylvian speech-cortex function and development. The entry lumps rolandic epilepsy with oral/speech dyspraxia and the bilateral perisylvian polymicrogyria presentation because the shared skeleton is coherent: SRPX2-dependent protein processing and SRPX2/uPAR network function converge on neuronal migration, tubulin acetylation, perisylvian cortical organization, and later epileptiform activity. It should not be expanded to all rolandic epilepsy, all developmental speech disorder, or all polymicrogyria.
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name: SRPX2-related Speech-Epilepsy-Polymicrogyria
creation_date: "2026-06-12T03:31:46Z"
category: Mendelian
description: >-
SRPX2-related speech-epilepsy-polymicrogyria is an X-linked
neurodevelopmental disorder boundary in which reported SRPX2 variants affect
rolandic/sylvian speech-cortex function and development. The entry lumps
rolandic epilepsy with oral/speech dyspraxia and the bilateral perisylvian
polymicrogyria presentation because the shared skeleton is coherent:
SRPX2-dependent protein processing and SRPX2/uPAR network function converge
on neuronal migration, tubulin acetylation, perisylvian cortical organization,
and later epileptiform activity. It should not be expanded to all rolandic
epilepsy, all developmental speech disorder, or all polymicrogyria.
parents:
- Rolandic epilepsy
- Polymicrogyria
- speech disorder
- malformation of cortical development
notes: >-
MONDO:0015587 labels rolandic epilepsy-speech dyspraxia syndrome, but no
disease_term is assigned because this curation intentionally includes the
SRPX2-associated bilateral perisylvian polymicrogyria boundary only where the
same SRPX2 speech-cortex migration mechanism applies. The ontology term does
not define the disease boundary.
references:
- reference: PMID:16497722
title: SRPX2 mutations in disorders of language cortex and cognition.
- reference: PMID:23831613
title: Tubacin prevents neuronal migration defects and epileptic activity caused by rat Srpx2 silencing in utero.
- reference: PMID:20858596
title: "Molecular networks implicated in speech-related disorders: FOXP2 regulates the SRPX2/uPAR complex."
- reference: PMID:17942002
title: Molecular evolution of the human SRPX2 gene that causes brain disorders of the Rolandic and Sylvian speech areas.
- reference: PMID:19682046
title: "From rolandic epilepsy to continuous spike-and-waves during sleep and Landau-Kleffner syndromes: insights into possible genetic factors."
- reference: PMID:36211152
title: The Genetic Landscape of Polymicrogyria.
- reference: PMID:28111201
title: Human iPSC-Derived Cerebral Organoids Model Cellular Features of Lissencephaly and Reveal Prolonged Mitosis of Outer Radial Glia.
pathophysiology:
- name: SRPX2 Missense Variation and Protein Processing Defect
description: >-
Reported SRPX2 missense variants affect a secreted sushi-repeat protein
expressed in neurons of the human brain, including the rolandic area. The
N327S variant was reported with rolandic seizures, oral/speech dyspraxia,
and intellectual disability, while Y72S was reported in a male with
rolandic seizures and bilateral perisylvian polymicrogyria. Cultured-cell
data suggest altered intracellular processing and protein misfolding.
role: trigger
genes:
- preferred_term: SRPX2
term:
id: hgnc:30668
label: SRPX2
cell_types:
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
biological_processes:
- preferred_term: protein folding
term:
id: GO:0006457
label: protein folding
modifier: DYSREGULATED
- preferred_term: protein N-linked glycosylation
term:
id: GO:0006487
label: protein N-linked glycosylation
modifier: DYSREGULATED
evidence:
- reference: PMID:16497722
reference_title: SRPX2 mutations in disorders of language cortex and cognition.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We have identified the Xq22 gene SRPX2 as being responsible for rolandic
seizures (RSs) associated with oral and speech dyspraxia and mental
retardation (MR).
explanation: >-
Establishes the original reported SRPX2 association with the
speech-epilepsy branch.
- reference: PMID:16497722
reference_title: SRPX2 mutations in disorders of language cortex and cognition.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A second mutation (Y72S) was identified within the first sushi domain of
SRPX2 in a male with RSs and bilateral perisylvian polymicrogyria and his
female relatives with mild MR or unaffected carrier status.
explanation: >-
Supports including bilateral perisylvian polymicrogyria within the
SRPX2-related boundary.
- reference: PMID:16497722
reference_title: SRPX2 mutations in disorders of language cortex and cognition.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In cultured cells, both mutations were associated with altered patterns of
intracellular processing, suggesting protein misfolding.
explanation: >-
Links the reported variants to altered protein handling in cells.
downstream:
- target: FOXP2-SRPX2-uPAR Speech-Cortex Regulatory Network Perturbation
description: >-
SRPX2 participates in a speech-related regulatory network involving FOXP2
and uPAR.
- target: Tubulin Acetylation and Neuronal Migration Defect
description: >-
SRPX2 loss or mutant SRPX2 impairs cortical neuronal migration and
alpha-tubulin acetylation in a developmental model.
- name: FOXP2-SRPX2-uPAR Speech-Cortex Regulatory Network Perturbation
description: >-
FOXP2 directly represses SRPX2 and uPAR promoter activity, and SRPX2-driven
mechanisms involve modified interaction with uPAR. This branch does not
make FOXP2 disease part of the SRPX2 entry; it records the regulatory
network that helps explain why SRPX2 phenotypes center on speech-related
rolandic/sylvian cortex.
role: modifier
genes:
- preferred_term: SRPX2
term:
id: hgnc:30668
label: SRPX2
biological_processes:
- preferred_term: regulation of DNA-templated transcription
term:
id: GO:0006355
label: regulation of DNA-templated transcription
modifier: DYSREGULATED
- preferred_term: cell adhesion
term:
id: GO:0007155
label: cell adhesion
modifier: DYSREGULATED
evidence:
- reference: PMID:20858596
reference_title: "Molecular networks implicated in speech-related disorders: FOXP2 regulates the SRPX2/uPAR complex."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Pathophysiological mechanisms driven by SRPX2 involve modified interaction
with the plasminogen activator receptor (uPAR).
explanation: >-
Supports the SRPX2/uPAR interaction branch.
- reference: PMID:20858596
reference_title: "Molecular networks implicated in speech-related disorders: FOXP2 regulates the SRPX2/uPAR complex."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
identified specific efficient FOXP2-binding sites in each of the promoter
regions of SRPX2 and uPAR.
explanation: >-
Supports direct transcriptional regulation of SRPX2 and uPAR by FOXP2.
- reference: PMID:20858596
reference_title: "Molecular networks implicated in speech-related disorders: FOXP2 regulates the SRPX2/uPAR complex."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Luciferase reporter assays demonstrated that FOXP2 expression yielded a
marked inhibition of SRPX2 (80.2%) and uPAR (77.5%) promoter activity.
explanation: >-
Quantitatively supports FOXP2-mediated repression of the SRPX2/uPAR
network.
downstream:
- target: Tubulin Acetylation and Neuronal Migration Defect
- name: Tubulin Acetylation and Neuronal Migration Defect
description: >-
In utero Srpx2 silencing in rat cortex impairs neuronal migration, and
wild-type but not mutant human SRPX2 rescues the migration phenotype while
increasing alpha-tubulin acetylation. This is the clearest module-conformant
branch and links SRPX2 to the microtubule-dependent neuronal migration
module rather than to a generic epilepsy module.
conforms_to: microtubule_dependent_neuronal_migration_failure#Microtubule-Based Neuronal Motility Failure
role: central_effector
cell_types:
- preferred_term: cortical neuron
term:
id: CL:0000540
label: neuron
biological_processes:
- preferred_term: neuron migration
term:
id: GO:0001764
label: neuron migration
modifier: DECREASED
- preferred_term: microtubule cytoskeleton organization
term:
id: GO:0000226
label: microtubule cytoskeleton organization
modifier: DYSREGULATED
- preferred_term: protein acetylation
term:
id: GO:0006473
label: protein acetylation
modifier: DYSREGULATED
evidence:
- reference: PMID:23831613
reference_title: Tubacin prevents neuronal migration defects and epileptic activity caused by rat Srpx2 silencing in utero.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Using an in utero Srpx2 silencing approach, we show that SRPX2 influences
neuronal migration in the developing rat cerebral cortex.
explanation: >-
Directly supports SRPX2-dependent neuronal migration in developing cortex.
- reference: PMID:23831613
reference_title: Tubacin prevents neuronal migration defects and epileptic activity caused by rat Srpx2 silencing in utero.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Wild-type, but not the mutant human SRPX2 proteins, rescued the neuronal
migration phenotype caused by Srpx2 silencing in utero, and increased
alpha-tubulin acetylation.
explanation: >-
Connects mutant SRPX2, neuronal migration rescue failure, and
alpha-tubulin acetylation.
downstream:
- target: Perisylvian Cortical Organization Failure
- target: Postnatal Epileptiform Activity
- name: Perisylvian Cortical Organization Failure
description: >-
The cortical-malformation branch is most specific for bilateral
perisylvian polymicrogyria, a migration-related malformation affecting
rolandic/sylvian speech areas. This endpoint justifies retaining PMG within
the SRPX2 entry only when connected to the same speech-cortex migration
skeleton.
conforms_to: microtubule_dependent_neuronal_migration_failure#Cortical Dyslamination and Neuronal Ectopia
role: outcome
locations:
- preferred_term: cerebral cortex
term:
id: UBERON:0000956
label: cerebral cortex
cell_types:
- preferred_term: cortical neuron
term:
id: CL:0000540
label: neuron
biological_processes:
- preferred_term: cerebral cortex development
term:
id: GO:0021987
label: cerebral cortex development
modifier: DYSREGULATED
- preferred_term: neuron migration
term:
id: GO:0001764
label: neuron migration
modifier: DECREASED
evidence:
- reference: PMID:16497722
reference_title: SRPX2 mutations in disorders of language cortex and cognition.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A second mutation (Y72S) was identified within the first sushi domain of
SRPX2 in a male with RSs and bilateral perisylvian polymicrogyria and his
female relatives with mild MR or unaffected carrier status.
explanation: >-
Supports bilateral perisylvian polymicrogyria as the structural branch.
- reference: PMID:36211152
reference_title: The Genetic Landscape of Polymicrogyria.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Polymicrogyria (PMG) is a relatively common complex malformation with
cortical development, characterized by an exorbitant number of abnormally
tiny gyri separated by shallow sulci. It is a neuronal migration disorder.
explanation: >-
Supports treating PMG as a neuronal-migration-related cortical
malformation.
downstream:
- target: Speech and Oromotor Impairment
- target: Postnatal Epileptiform Activity
- name: Speech and Oromotor Impairment
description: >-
The rolandic/sylvian and perisylvian cortical involvement produces speech
and oral motor impairment, including oral/speech dyspraxia, delayed or
impaired language, and variable cognitive disability.
role: outcome
locations:
- preferred_term: cerebral cortex
term:
id: UBERON:0000956
label: cerebral cortex
biological_processes:
- preferred_term: nervous system development
term:
id: GO:0007399
label: nervous system development
modifier: DYSREGULATED
evidence:
- reference: PMID:16497722
reference_title: SRPX2 mutations in disorders of language cortex and cognition.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The involvement of SRPX2 in these disorders suggests an important role for
SRPX2 in the perisylvian region critical for language and cognitive
development.
explanation: >-
Links SRPX2 to perisylvian language and cognitive development.
- name: Postnatal Epileptiform Activity
description: >-
Disrupted SRPX2-dependent cortical development can be followed by postnatal
epileptiform activity. This node records the seizure/epileptiform endpoint
without asserting a specific ion-channel or excitation-inhibition mechanism.
role: outcome
cell_types:
- preferred_term: cortical neuron
term:
id: CL:0000540
label: neuron
biological_processes:
- preferred_term: nervous system development
term:
id: GO:0007399
label: nervous system development
modifier: DYSREGULATED
evidence:
- reference: PMID:23831613
reference_title: Tubacin prevents neuronal migration defects and epileptic activity caused by rat Srpx2 silencing in utero.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Following in utero Srpx2 silencing, spontaneous epileptiform activity was
recorded post-natally.
explanation: >-
Supports epileptiform activity as a downstream consequence of in utero
Srpx2 perturbation.
- reference: PMID:19682046
reference_title: "From rolandic epilepsy to continuous spike-and-waves during sleep and Landau-Kleffner syndromes: insights into possible genetic factors."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Recent reports on the involvement of the SRPX2 and ELP4 genes with
possible roles in cell motility, migration, and adhesion have provided
first insights into the complex molecular bases of childhood focal
epilepsies.
explanation: >-
Review-level support connects SRPX2-related motility/migration biology to
childhood focal epilepsy mechanisms.
phenotypes:
- name: Rolandic Seizures / Focal Epilepsy
description: >-
Reported SRPX2 disease includes rolandic seizures and childhood focal
epilepsy-spectrum presentations.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
onset:
onset_category: CHILDHOOD
evidence:
- reference: PMID:16497722
reference_title: SRPX2 mutations in disorders of language cortex and cognition.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We have identified the Xq22 gene SRPX2 as being responsible for rolandic
seizures (RSs) associated with oral and speech dyspraxia and mental
retardation (MR).
explanation: >-
Supports rolandic seizures as part of the reported SRPX2 phenotype.
- name: EEG With Centrotemporal Epileptiform Discharges
description: >-
Centrotemporal spike-wave EEG features are part of the broader rolandic
epilepsy spectrum relevant to SRPX2 presentations.
phenotype_term:
preferred_term: EEG with centrotemporal epileptiform discharges
term:
id: HP:0033721
label: EEG with centrotemporal epileptiform discharges
evidence:
- reference: PMID:19682046
reference_title: "From rolandic epilepsy to continuous spike-and-waves during sleep and Landau-Kleffner syndromes: insights into possible genetic factors."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
the benign childhood epilepsy with centrotemporal spikes (BCECTS) or
benign rolandic epilepsy, are different entities that are considered as
part of a single continuous spectrum of disorders.
explanation: >-
Supports the centrotemporal spike-wave context of the childhood focal
epilepsy spectrum.
- name: Speech Apraxia
description: >-
Speech dyspraxia is central to the speech-epilepsy branch of reported
SRPX2 disease.
phenotype_term:
preferred_term: Speech apraxia
term:
id: HP:0011098
label: Speech apraxia
evidence:
- reference: PMID:16497722
reference_title: SRPX2 mutations in disorders of language cortex and cognition.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
rolandic seizures (RSs) associated with oral and speech dyspraxia and
mental retardation (MR).
explanation: >-
Supports speech dyspraxia as a core feature.
- name: Oromotor Apraxia
description: >-
Oral dyspraxia is described with the rolandic seizure phenotype.
phenotype_term:
preferred_term: Oromotor apraxia
term:
id: HP:0007301
label: Oromotor apraxia
evidence:
- reference: PMID:16497722
reference_title: SRPX2 mutations in disorders of language cortex and cognition.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
rolandic seizures (RSs) associated with oral and speech dyspraxia and
mental retardation (MR).
explanation: >-
Supports oral dyspraxia as an oromotor phenotype.
- name: Bilateral Perisylvian Polymicrogyria
description: >-
The structural cortical malformation branch is bilateral perisylvian
polymicrogyria affecting speech-related cortex.
phenotype_term:
preferred_term: Bilateral perisylvian polymicrogyria
term:
id: HP:0032407
label: Bilateral perisylvian polymicrogyria
evidence:
- reference: PMID:16497722
reference_title: SRPX2 mutations in disorders of language cortex and cognition.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
bilateral perisylvian polymicrogyria and his female relatives with mild MR
or unaffected carrier status.
explanation: >-
Supports bilateral perisylvian polymicrogyria in the reported SRPX2
structural branch.
- name: Intellectual Disability
description: >-
Cognitive impairment is variable; the original abstract uses historical
terminology for intellectual disability.
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: PMID:16497722
reference_title: SRPX2 mutations in disorders of language cortex and cognition.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
rolandic seizures (RSs) associated with oral and speech dyspraxia and
mental retardation (MR).
explanation: >-
Supports intellectual disability using the source's historical term.
genetic:
- name: SRPX2
association: Reported causal variants with unresolved variant-specific confidence
gene_term:
preferred_term: SRPX2
term:
id: hgnc:30668
label: SRPX2
evidence:
- reference: PMID:16497722
reference_title: SRPX2 mutations in disorders of language cortex and cognition.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We have identified the Xq22 gene SRPX2 as being responsible for rolandic
seizures (RSs) associated with oral and speech dyspraxia and mental
retardation (MR).
explanation: >-
Supports the reported SRPX2 gene-disease association for the
speech-epilepsy branch.
- reference: PMID:16497722
reference_title: SRPX2 mutations in disorders of language cortex and cognition.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A second mutation (Y72S) was identified within the first sushi domain of
SRPX2 in a male with RSs and bilateral perisylvian polymicrogyria and his
female relatives with mild MR or unaffected carrier status.
explanation: >-
Supports the reported SRPX2 gene-disease association for the PMG branch.
treatments:
- name: Anti-Seizure Medication
description: >-
Standard seizure management is symptomatic; tubacin evidence remains
preclinical and does not establish a human therapy.
treatment_term:
preferred_term: Anticonvulsant Therapy
term:
id: NCIT:C64172
label: Anticonvulsant Therapy
- name: Speech Therapy
description: >-
Supportive speech-language therapy is relevant for speech apraxia and
speech/language impairment.
treatment_term:
preferred_term: speech therapy
term:
id: MAXO:0000930
label: speech therapy
- name: Occupational Therapy
description: >-
Supportive occupational therapy may be appropriate for associated motor,
developmental, or functional impairment.
treatment_term:
preferred_term: occupational therapy
term:
id: MAXO:0001351
label: occupational therapy
- name: Genetic Counseling
description: >-
X-linked inheritance, variable female expression, and uncertain
variant-specific confidence make genetic counseling important after a
reported SRPX2 variant is found.
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
discussions:
- discussion_id: gap_srpx2_variant_causality_and_lumping
prompt: >-
Which SRPX2 variants have sufficient modern segregation, population,
functional, and replication evidence to support a single disease entry with
speech-epilepsy and bilateral perisylvian PMG branches?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#SRPX2 Missense Variation and Protein Processing Defect
- pathophysiology#Perisylvian Cortical Organization Failure
rationale: >-
The original abstracts support reported N327S and Y72S branches, but the
Falcon report flagged later concern about variant-specific causality for
N327S. For curation, this means SRPX2 should stay as a coherent
mechanism-bound entry while variant-level confidence and subtype branching
remain open until modern ClinVar/gnomAD/segregation and rescue evidence are
reviewed.
evidence:
- reference: PMID:16497722
reference_title: SRPX2 mutations in disorders of language cortex and cognition.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A second mutation (Y72S) was identified within the first sushi domain of
SRPX2 in a male with RSs and bilateral perisylvian polymicrogyria and his
female relatives with mild MR or unaffected carrier status.
explanation: >-
Shows variable expression or carrier status within the reported PMG
branch, motivating careful variant-level interpretation.
- reference: PMID:17942002
reference_title: Molecular evolution of the human SRPX2 gene that causes brain disorders of the Rolandic and Sylvian speech areas.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The R75K substitution occurred in the first sushi domain of SRPX2, only
three amino acid residues away from a previously reported disease-causing
mutation (Y72S).
explanation: >-
Supports focusing variant interpretation on the first sushi domain while
keeping functional consequences open.
proposed_experiments:
- experiment_id: exp_srpx2_variant_reclassification_panel
name: SRPX2 variant reclassification and rescue panel
description: >-
Reassess reported SRPX2 variants with current population frequencies,
segregation, X-inactivation data, protein-processing assays, and
standardized rescue of SRPX2 knockdown or knockout phenotypes. Include
N327S, Y72S, nearby first-sushi-domain variants, and matched benign
controls.
experiment_type:
preferred_term: variant reclassification and functional rescue experiment
perturbations:
- name: SRPX2 variant knock-in or rescue
target: pathophysiology#SRPX2 Missense Variation and Protein Processing Defect
genes:
- preferred_term: SRPX2
term:
id: hgnc:30668
label: SRPX2
description: >-
Introduce or rescue individual SRPX2 variants in a shared assay
background to compare protein processing, migration, and tubulin
acetylation.
readouts:
- name: Protein processing and neuronal migration rescue
target: pathophysiology#Tubulin Acetylation and Neuronal Migration Defect
biological_processes:
- preferred_term: neuron migration
term:
id: GO:0001764
label: neuron migration
modifier: DECREASED
- preferred_term: protein acetylation
term:
id: GO:0006473
label: protein acetylation
modifier: DYSREGULATED
assays:
- preferred_term: cell migration assay
- preferred_term: immunoblot assay
direction: POSITIVE
controls:
- name: Wild-type SRPX2 rescue
description: Rescue with wild-type human SRPX2.
- name: Benign variant controls
description: Variants with population frequency incompatible with disease causality.
decision_criterion: >-
A variant-specific branch is supported only when the variant segregates
with disease and reproducibly fails to rescue protein-processing,
migration, or tubulin-acetylation phenotypes relative to wild type.
would_support:
- pathophysiology#SRPX2 Missense Variation and Protein Processing Defect
- pathophysiology#Tubulin Acetylation and Neuronal Migration Defect
- discussion_id: gap_srpx2_human_model_translatability
prompt: >-
Do SRPX2 migration, tubulin-acetylation, and epileptiform phenotypes
observed in rat in utero silencing translate to human perisylvian cortical
development and patient-relevant speech-cortex biology?
kind: HUMAN_MODEL_MISMATCH
status: OPEN
attaches_to:
- pathophysiology#Tubulin Acetylation and Neuronal Migration Defect
- pathophysiology#Perisylvian Cortical Organization Failure
- pathophysiology#Postnatal Epileptiform Activity
rationale: >-
The strongest mechanistic evidence is a rodent in utero silencing and
rescue model. The Falcon report did not identify direct SRPX2 patient iPSC
or organoid evidence. Human cortical organoids cannot fully model speech
behavior, but they can test whether SRPX2 variants perturb human cortical
neuronal migration, tubulin acetylation, and perisylvian-like cortical
organization before seizure phenotypes are inferred.
evidence:
- reference: PMID:23831613
reference_title: Tubacin prevents neuronal migration defects and epileptic activity caused by rat Srpx2 silencing in utero.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Using an in utero Srpx2 silencing approach, we show that SRPX2 influences
neuronal migration in the developing rat cerebral cortex.
explanation: >-
Identifies the model-organism mechanism whose human translation remains
open.
- reference: PMID:28111201
reference_title: Human iPSC-Derived Cerebral Organoids Model Cellular Features of Lissencephaly and Reveal Prolonged Mitosis of Outer Radial Glia.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Recent work has uncovered critical cellular and molecular differences
between cortical development in humans and mice, further underscoring the
need to develop human model systems.
explanation: >-
Supports explicit human/model mismatch handling for cortical-development
mechanisms.
proposed_experiments:
- experiment_id: exp_srpx2_isogenic_cortical_organoid_migration_acetylation
name: SRPX2 isogenic cortical-organoid migration and tubulin-acetylation experiment
description: >-
Generate patient-derived or engineered human cortical organoids carrying
SRPX2 N327S, Y72S, loss-of-function, and corrected alleles, then compare
cortical neuron migration, alpha-tubulin acetylation, SRPX2/uPAR pathway
readouts, and network activity against the rat in utero model.
experiment_type:
preferred_term: isogenic cortical organoid migration experiment
model_systems:
- name: SRPX2 human iPSC-derived cortical organoid
description: >-
Human cortical organoid or cortical assembloid model with neural
progenitors and migrating cortical neurons, used for migration and
network-readout assays rather than speech-behavior phenotyping.
experimental_model_type: ORGANOID
namo_type: namo:Organoid
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
tissue_term:
preferred_term: cerebral cortex
term:
id: UBERON:0000956
label: cerebral cortex
cell_types:
- preferred_term: cortical neuron
term:
id: CL:0000540
label: neuron
- preferred_term: neural progenitor cell
term:
id: CL:0011020
label: neural progenitor cell
conditions:
- SRPX2-related speech-epilepsy-polymicrogyria
- neuronal migration defect
- perisylvian polymicrogyria
cell_source: Patient-derived or CRISPR-engineered human induced pluripotent stem cells
culture_system: Three-dimensional cortical organoid or cortical assembloid with migration and activity assays
perturbations:
- name: SRPX2 variant correction or knock-in
target: pathophysiology#SRPX2 Missense Variation and Protein Processing Defect
genes:
- preferred_term: SRPX2
term:
id: hgnc:30668
label: SRPX2
description: >-
Correct patient variants or introduce reported SRPX2 variants into an
isogenic human iPSC background.
readouts:
- name: Neuronal migration and alpha-tubulin acetylation
target: pathophysiology#Tubulin Acetylation and Neuronal Migration Defect
biological_processes:
- preferred_term: neuron migration
term:
id: GO:0001764
label: neuron migration
modifier: DECREASED
- preferred_term: protein acetylation
term:
id: GO:0006473
label: protein acetylation
modifier: DYSREGULATED
assays:
- preferred_term: live-cell imaging assay
- preferred_term: immunostaining
direction: POSITIVE
- name: Network excitability readout
target: pathophysiology#Postnatal Epileptiform Activity
biological_processes:
- preferred_term: trans-synaptic signaling
term:
id: GO:0099537
label: trans-synaptic signaling
modifier: DYSREGULATED
assays:
- preferred_term: multielectrode array recording
direction: POSITIVE
controls:
- name: Isogenic corrected organoids
description: Matched organoids in which the SRPX2 variant is corrected.
- name: Isogenic knock-in organoids
description: Wild-type-background organoids carrying the introduced SRPX2 variant.
decision_criterion: >-
Human translation is supported if SRPX2 mutant organoids show migration
and tubulin-acetylation defects matching the rat model and rescued by
variant correction or wild-type SRPX2. The seizure branch remains
inferential unless network hyperexcitability is reproducibly detected.
would_support:
- pathophysiology#Tubulin Acetylation and Neuronal Migration Defect
- pathophysiology#Perisylvian Cortical Organization Failure
- pathophysiology#Postnatal Epileptiform Activity
- discussion_id: gap_srpx2_tubacin_preclinical_translation
prompt: >-
Does tubacin prevention of rat Srpx2-silencing phenotypes identify a
realistic therapeutic mechanism for human SRPX2 disease, or only a
developmental proof of principle?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Tubulin Acetylation and Neuronal Migration Defect
- pathophysiology#Postnatal Epileptiform Activity
rationale: >-
Tubacin prevention is mechanistically important, but it is prenatal,
model-organism, pathway-level evidence. It should not be curated as a
disease-modifying human treatment without dose, timing, safety, specificity,
and human-cell rescue evidence.
evidence:
- reference: PMID:23831613
reference_title: Tubacin prevents neuronal migration defects and epileptic activity caused by rat Srpx2 silencing in utero.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The neuronal migration defects and the post-natal epileptic consequences
were prevented early in embryos by maternal administration of tubulin
deacetylase inhibitor tubacin.
explanation: >-
Supports tubacin as a preclinical pathway probe, not a current human
therapy.
proposed_experiments:
- experiment_id: exp_srpx2_tubacin_human_cell_rescue_window
name: SRPX2 tubacin rescue window and specificity experiment
description: >-
Test tubacin and more selective tubulin-acetylation modulators in SRPX2
human neural progenitor and cortical organoid models across developmental
windows, measuring migration rescue, alpha-tubulin acetylation,
off-target transcriptional effects, and network activity.
experiment_type:
preferred_term: preclinical rescue-window experiment
readouts:
- name: Rescue and toxicity readouts
target: pathophysiology#Tubulin Acetylation and Neuronal Migration Defect
biological_processes:
- preferred_term: neuron migration
term:
id: GO:0001764
label: neuron migration
modifier: DECREASED
- preferred_term: protein acetylation
term:
id: GO:0006473
label: protein acetylation
modifier: DYSREGULATED
assays:
- preferred_term: migration assay
- preferred_term: cell viability assay
direction: POSITIVE
controls:
- name: Vehicle-treated mutant and corrected controls
description: Matched controls to distinguish rescue from nonspecific toxicity.
decision_criterion: >-
Therapeutic plausibility increases only if a safe exposure window rescues
human-cell migration and acetylation defects without broad toxicity or
nonspecific developmental disruption.
would_support:
- pathophysiology#Tubulin Acetylation and Neuronal Migration Defect
SRPX2-related disease is a rare X-linked neurodevelopmental disorder spectrum centered on (i) focal (rolandic/centrotemporal) epilepsy, (ii) speech/oromotor dyspraxia and language impairment, and (iii) in some individuals, bilateral perisylvian polymicrogyria (PMG) involving speech-related cortical regions. Current mechanistic understanding places SRPX2 within a FOXP2-regulated network and links SRPX2 dysfunction to abnormal neuronal migration and altered tubulin acetylation, with preclinical evidence that pathway-targeted intervention (tubacin) can prevent downstream epileptiform activity in a rodent developmental model. (rudolf2009fromrolandicepilepsy pages 1-2, roll2010molecularnetworksimplicated pages 1-2, salmi2013tubacinpreventsneuronal pages 1-2)
“SRPX2-related Speech–Epilepsy–Polymicrogyria Boundary” refers to a clinical continuum spanning rolandic epilepsy with speech dyspraxia (historically termed RESDX in the cited literature) and more overt perisylvian cortical malformation phenotypes (bilateral perisylvian PMG) with epilepsy and neurodevelopmental impairment. (rudolf2009fromrolandicepilepsy pages 1-2, bernardo2024xlinkedepilepsiesa pages 19-21)
Not found in retrieved context: ICD-10/ICD-11 codes, MeSH IDs, and a MONDO term explicitly corresponding to the user’s exact label (“speech-epilepsy-polymicrogyria boundary”).
The information summarized here is derived from a mix of: * Aggregated resources: OpenTargets disease–gene associations (OpenTargets Search: -SRPX2) * Primary mechanistic research: FOXP2→SRPX2/uPAR regulation (Human Molecular Genetics, 2010) and rodent in utero silencing/rescue studies (Brain, 2013) (roll2010molecularnetworksimplicated pages 1-2, salmi2013tubacinpreventsneuronal pages 1-2) * Clinical/genetics reviews: epilepsy-aphasia/rolandic spectrum and X-linked PMG gene reviews (2009–2024) (rudolf2009fromrolandicepilepsy pages 1-2, bernardo2024xlinkedepilepsiesa pages 19-21)
Primary causal factor: pathogenic variation in SRPX2 (X-linked) in a subset of affected families, with phenotypes involving epilepsy and/or structural malformation of speech cortex. The Brain 2013 paper explicitly frames the prior human findings as: “Two missense mutations in the sushi repeat-containing protein SRPX2 had been previously identified in epileptic disorders with or without structural developmental alteration of the speech cortex.” (salmi2013tubacinpreventsneuronal pages 1-2)
Important nuance: the causal role of at least one reported missense variant (p.N327S) has been questioned due to co-inheritance with another missense change in most affected members of that family. (salmi2013tubacinpreventsneuronal pages 2-2)
Environmental risk factors / protective factors / gene–environment interactions: Not specifically described in the retrieved SRPX2-focused context. (Evidence gap)
Below are key phenotypes supported by the retrieved literature; quantitative penetrance/frequency estimates for SRPX2-specific cohorts were not available in the extracted passages.
1) Speech and language impairment / dyspraxia * Described as speech delay, verbal/oral dyspraxia, and oro-facial dyspraxia, often central to the syndrome designation. (rudolf2009fromrolandicepilepsy pages 1-2, bernardo2024xlinkedepilepsiesa pages 19-21) * Suggested HPO terms (mapping suggestion; not asserted as extracted HPO annotations): * HP:0000750 Speech delay * HP:0002465 Dysarthria * HP:0011445 Oromotor apraxia * HP:0000738 Aphasia / language impairment (broad)
2) Epilepsy (rolandic/centrotemporal focal seizures; spectrum overlap) * SRPX2 is linked to rolandic epilepsy with centrotemporal spikes in the broader rolandic/epilepsy-aphasia spectrum review context. (rudolf2009fromrolandicepilepsy pages 1-2) * Suggested HPO terms: * HP:0001250 Seizures * HP:0002373 Febrile seizures (if present; not established in extracted SRPX2 passages) * HP:0020219 Centrotemporal spikes (EEG) (phenotype representation)
3) Polymicrogyria / bilateral perisylvian polymicrogyria * A disease-associated SRPX2 mutation (Y72) is discussed in the context of “rolandic seizures and bilateral perisylvian polymicrogyria.” (royer2007molecularevolutionof pages 2-3) * Suggested HPO terms: * HP:0002126 Polymicrogyria * HP:0002325 Bilateral perisylvian polymicrogyria
4) Neurodevelopmental impairment / intellectual disability (variable) * A 2009 review states the rolandic epilepsy–speech dyspraxia presentation includes “variable degrees of mental retardation” (historical terminology). (rudolf2009fromrolandicepilepsy pages 1-2) * Suggested HPO terms: * HP:0001249 Intellectual disability * HP:0001263 Global developmental delay
Direct QoL instrument data (EQ-5D/SF-36/PROMIS) were not identified in retrieved evidence; however, the clinical features (speech dyspraxia, epilepsy, PMG) are expected to significantly impact communication and daily functioning. (Evidence gap)
Variant types in evidence: missense variants. (salmi2013tubacinpreventsneuronal pages 2-2)
Population allele frequencies / ClinVar classifications: not available in retrieved context. (Evidence gap)
Rodent model evidence supports a loss-of-normal-developmental-function interpretation: * “Wild-type, but not the mutant human SRPX2 proteins, rescued the neuronal migration phenotype caused by Srpx2 silencing in utero” and increased alpha-tubulin acetylation. (salmi2013tubacinpreventsneuronal pages 1-2)
Not established for SRPX2 in retrieved context. * A 2024 X-linked epilepsy review emphasizes that “epigenetic regulation and X-chromosome inactivation” can complicate X-linked genotype–phenotype correlations generally, which is relevant to interpreting female carriers, but is not SRPX2-specific evidence in the extracted lines. (bernardo2024xlinkedepilepsiesa pages 22-23)
No SRPX2-specific environmental, lifestyle, toxin, or infectious contributors were identified in the retrieved texts. (Evidence gap)
Two complementary mechanistic frames emerge from the retrieved evidence:
Suggested GO biological process terms (mechanism mapping suggestions): * GO:0006355 regulation of transcription, DNA-templated * GO:0007399 nervous system development
The 2013 Brain study provides a causal chain in a developmental rodent model: 1) Trigger: in utero Srpx2 knockdown 2) Upstream cellular process: abnormal neuronal migration during cortical development 3) Biochemical link: altered alpha-tubulin acetylation (wild-type SRPX2 increases acetylation; mutant does not rescue) (salmi2013tubacinpreventsneuronal pages 1-2) 4) Downstream electrophysiology: “spontaneous epileptiform activity” recorded postnatally (salmi2013tubacinpreventsneuronal pages 1-2) 5) Pharmacologic prevention in utero: “The neuronal migration defects and the post-natal epileptic consequences were prevented early in embryos by maternal administration of tubulin deacetylase inhibitor tubacin.” (salmi2013tubacinpreventsneuronal pages 1-2)
Suggested GO terms: * GO:0001764 neuron migration * GO:0000226 microtubule cytoskeleton organization
Suggested cell types (CL term suggestions): * CL:0000540 neuron * CL:0000127 cortical neuron (more specific mapping as appropriate)
A 2024 review of X-linked epilepsies frames SRPX2 as a gene initially linked to rolandic seizures and language/oromotor phenotypes and places it among key X-linked PMG genes, supporting the view that SRPX2 sits at a boundary between functional epilepsy-aphasia phenotypes and structural migration/cortical organization disorders. (bernardo2024xlinkedepilepsiesa pages 19-21)
Suggested UBERON terms (mapping suggestions): * UBERON:0000955 brain * UBERON:0001870 cerebral cortex * UBERON:0002771 frontal lobe operculum / perisylvian cortex (depending on ontology granularity)
No robust SRPX2-specific prevalence/incidence estimates were identified in the retrieved texts.
A relevant background statistic from a 2024 review (X-linked PMG, not SRPX2-specific): epilepsy is observed in approximately 80% of X-linked PMG cases. (bernardo2024xlinkedepilepsiesa pages 19-21)
SRPX2-related phenotypes lie at the intersection of epilepsy-aphasia spectrum and malformations of cortical development, suggesting a practical diagnostic approach: * EEG to identify centrotemporal spikes / focal epileptiform patterns in rolandic epilepsy presentations (review-level). (rudolf2009fromrolandicepilepsy pages 1-2) * Brain MRI to evaluate for bilateral perisylvian polymicrogyria and related cortical malformations where clinically indicated. The SRPX2 disease concept explicitly includes cases “with or without structural developmental alteration of the speech cortex.” (salmi2013tubacinpreventsneuronal pages 1-2)
A PMG review recommends exploring genetic testing and notes challenges including de novo variants, mosaicism, and CNVs in PMG broadly; it explicitly includes SRPX2 in a suggested malformations-of-cortical-development gene panel. (james2022thegeneticlandscape pages 7-8)
In practice (inference consistent with review statements), SRPX2 evaluation is typically performed via: * NGS epilepsy and/or malformations-of-cortical-development panels including SRPX2 (james2022thegeneticlandscape pages 7-8) * WES/WGS when phenotype is broader or when panel testing is negative (review-level general recommendation in PMG). (james2022thegeneticlandscape pages 7-8)
Not systematically enumerated in retrieved context; however, SRPX2 sits within the set of genes implicated in PMG and epilepsy-aphasia spectrum. The 2024 X-linked epilepsy review highlights multiple X-linked PMG genes and emerging genes; SRPX2 is discussed among these. (bernardo2024xlinkedepilepsiesa pages 19-21)
SRPX2-specific long-term outcomes, mortality, and validated prognostic factors were not identified in the retrieved context.
Based on syndrome descriptions, disability burden is primarily driven by seizure control, degree of speech/oromotor impairment, and presence/extent of cortical malformation and intellectual disability (review-level). (rudolf2009fromrolandicepilepsy pages 1-2, bernardo2024xlinkedepilepsiesa pages 19-21)
No SRPX2-specific controlled treatment studies were identified in retrieved texts.
For polymicrogyria broadly, a 2022 review summarizes real-world management as symptomatic: * “The first-line treatment for those with seizures is anti-seizure medications.” (james2022thegeneticlandscape pages 7-8) * Surgical candidacy may depend on lesion laterality/extent: unilateral focal PMG may be considered for resective surgery; bilateral PMG is generally not a good candidate for resection (review-level). (james2022thegeneticlandscape pages 7-8) * Supportive therapies: “Occupational therapy, physiotherapy, and speech therapy may help” some affected individuals. (james2022thegeneticlandscape pages 7-8)
Suggested MAXO terms (mapping suggestions): * MAXO:0000016 antiepileptic drug therapy * MAXO:0000757 speech therapy * MAXO:0000445 occupational therapy
A key preclinical development is the 2013 Brain study showing in utero prevention of downstream epileptiform activity in a rodent model: * “The neuronal migration defects and the post-natal epileptic consequences were prevented… by maternal administration of tubulin deacetylase inhibitor tubacin.” (salmi2013tubacinpreventsneuronal pages 1-2)
This is not a current human therapy, but it provides mechanistic support for targeting microtubule/tubulin acetylation pathways in SRPX2-related developmental epilepsy mechanisms.
No established primary prevention exists beyond genetic counseling for families.
For PMG broadly, the 2022 review highlights the importance of genetic testing and counseling and notes that risk assessment depends on inheritance and the identified cause. (james2022thegeneticlandscape pages 7-8)
No naturally occurring SRPX2-related disease in other species was identified in the retrieved context.
A mechanistically informative rat in utero gene-silencing model exists: * Srpx2 silencing in utero produces neuronal migration defects and postnatal epileptiform activity, with rescue by wild-type human SRPX2 but not mutant SRPX2; tubacin prevents defects and epileptiform outcomes. (salmi2013tubacinpreventsneuronal pages 1-2)
Limitation: No 2023–2024 primary SRPX2 case series or variant reclassification papers were successfully retrieved in the current tool run; therefore, recent patient counts, novel variants, and modern ACMG/ClinVar interpretations are not included here.
| Topic | Summary | Publication / year | PMID / identifier(s) | URL | Citation |
|---|---|---|---|---|---|
| Disease names / synonyms / identifiers | Evidence supports the SRPX2-associated disease spectrum including Rolandic epilepsy–speech dyspraxia / RESDX / rolandic epilepsy-speech dyspraxia syndrome and bilateral perisylvian polymicrogyria (BPP) / congenital bilateral perisylvian syndrome. OMIM numbers explicitly mentioned for SRPX2 (OMIM 300642), Rolandic epilepsy–speech dyspraxia (OMIM 300643), and bilateral perisylvian polymicrogyria (OMIM 300388). Open Targets context lists MONDO_0015587 rolandic epilepsy-speech dyspraxia syndrome and Orphanet 163721 Rolandic epilepsy - speech dyspraxia. | Hum Mol Genet 2010; Open Targets context; IJMS review 2024 | PMID not shown in context for 2010 paper; MONDO_0015587; Orphanet 163721; OMIM 300642/300643/300388 | https://doi.org/10.1093/hmg/ddq415 | (roll2010molecularnetworksimplicated pages 1-2, OpenTargets Search: -SRPX2, bernardo2024xlinkedepilepsiesa pages 19-21) |
| Inheritance | Reported as an X-linked syndrome for SRPX2-related RESDX; females may show milder or variable manifestations, plausibly influenced by skewed X-inactivation. PMG literature notes familial PMG can be autosomal dominant, autosomal recessive, or X-linked, but the SRPX2 disorder specifically is X-linked in the cited syndrome reports. | Epilepsia 2009; IJMS review 2024; PMG review 2022 | PMID not shown in context | https://doi.org/10.1111/j.1528-1167.2009.02214.x ; https://doi.org/10.3390/ijms25074110 ; https://doi.org/10.4103/aian.aian_97_22 | (rudolf2009fromrolandicepilepsy pages 1-2, bernardo2024xlinkedepilepsiesa pages 19-21, james2022thegeneticlandscape pages 7-8) |
| Core phenotype: speech / oromotor | Recurrent phenotypes across reports/reviews include speech delay, verbal/oral dyspraxia, oro-facial dyspraxia, and language-cortex dysfunction. These features are central to the named syndrome and often accompany epilepsy; intellectual disability may be variable. | Epilepsia 2009; IJMS review 2024 | PMID not shown in context | https://doi.org/10.1111/j.1528-1167.2009.02214.x ; https://doi.org/10.3390/ijms25074110 | (rudolf2009fromrolandicepilepsy pages 1-2, bernardo2024xlinkedepilepsiesa pages 19-21) |
| Core phenotype: epilepsy | Seizures are typically rolandic/centrotemporal in the classic syndrome. Reviews connect SRPX2 to focal epilepsies of the rolandic/sylvian speech areas. In X-linked PMG broadly, epilepsy is observed in ~80% of cases. | Epilepsia 2009; IJMS review 2024 | PMID not shown in context | https://doi.org/10.1111/j.1528-1167.2009.02214.x ; https://doi.org/10.3390/ijms25074110 | (rudolf2009fromrolandicepilepsy pages 1-2, bernardo2024xlinkedepilepsiesa pages 19-21) |
| Core phenotype: cortical malformation | SRPX2 is also linked to bilateral perisylvian polymicrogyria, a developmental malformation of the speech cortex; reviews note SRPX2 among the principal X-linked PMG genes. | BMC Genet 2007; IJMS review 2024; PMG review 2022 | PMID not shown in context | https://doi.org/10.1186/1471-2156-8-72 ; https://doi.org/10.3390/ijms25074110 ; https://doi.org/10.4103/aian.aian_97_22 | (royer2007molecularevolutionof pages 2-3, bernardo2024xlinkedepilepsiesa pages 19-21, james2022thegeneticlandscape pages 7-8) |
| Key SRPX2 variants | Two historically emphasized missense variants are p.N327S (reported with rolandic epilepsy and verbal dyspraxia) and p.Y72S (reported with bilateral perisylvian polymicrogyria / rolandic seizures). The 2013 Brain study notes that the direct causal role of p.N327S has been questioned because of co-inheritance of another missense variant in most affected members. | Brain 2013; BMC Genet 2007 | PMID not shown in context | https://doi.org/10.1093/brain/awt161 ; https://doi.org/10.1186/1471-2156-8-72 | (salmi2013tubacinpreventsneuronal pages 2-2, royer2007molecularevolutionof pages 2-3, salmi2013tubacinpreventsneuronal pages 1-2) |
| FOXP2 network variants (mechanistic context) | FOXP2 p.R553H abolishes repression/binding effects on SRPX2/uPAR regulatory sites; FOXP2 p.M406T causes partial loss of nuclear localization and significant loss of SRPX2 promoter repression. These FOXP2 variants are mechanistic network findings rather than primary SRPX2 disease alleles. | Hum Mol Genet 2010 | PMID not shown in context | https://doi.org/10.1093/hmg/ddq415 | (roll2010molecularnetworksimplicated pages 7-9, roll2010molecularnetworksimplicated pages 5-7, roll2010molecularnetworksimplicated pages 1-2) |
| Mechanism: FOXP2 represses SRPX2/uPAR | FOXP2 directly down-regulates SRPX2 and uPAR; reported quantitative effects include 43.6% reduction of SRPX2 transcripts, 38.6% reduction of uPAR transcripts, and inhibition of SRPX2 and uPAR promoter activity by about 80.2% and 77.5%, respectively. This supports a FOXP2→SRPX2/uPAR speech-disorder network. | Hum Mol Genet 2010 | PMID not shown in context | https://doi.org/10.1093/hmg/ddq415 | (roll2010molecularnetworksimplicated pages 1-2) |
| Mechanism: neuronal migration / tubulin acetylation | In utero Srpx2 silencing in rat cortex causes neuronal migration defects and later spontaneous epileptiform activity. Wild-type, but not mutant, human SRPX2 rescues the migration phenotype and increases alpha-tubulin acetylation, linking SRPX2 dysfunction to cortical development. | Brain 2013 | PMID not shown in context | https://doi.org/10.1093/brain/awt161 | (salmi2013tubacinpreventsneuronal pages 1-2) |
| Mechanism / experimental rescue | Maternal treatment with the tubulin deacetylase inhibitor tubacin prevented both the migration abnormalities and postnatal epileptiform consequences in the rat model, providing proof-of-principle for pathway-targeted rescue in a developmental model. This remains preclinical, not a human standard of care. | Brain 2013 | PMID not shown in context | https://doi.org/10.1093/brain/awt161 | (salmi2013tubacinpreventsneuronal pages 1-2, salmi2013tubacinpreventsneuronal pages 2-2) |
| Recent review perspective (2023–2024) | Recent reviews continue to place SRPX2 among important X-linked PMG and X-linked epilepsy genes. The 2024 review states SRPX2 was initially related to Rolandic seizures, ID, speech delay, oro-facial dyspraxia, and abnormalities in brain speech areas; the 2023 review discusses X-linked neuronal migration disorders and emphasizes limited epidemiologic data overall. | Int J Mol Sci 2024; Int J Dev Neurosci 2023 | PMID not shown in context | https://doi.org/10.3390/ijms25074110 ; https://doi.org/10.1002/jdn.10290 | (bernardo2024xlinkedepilepsiesa pages 19-21, edey2023x‐linkedneuronalmigration pages 5-6) |
Table: This table condenses the main disease names, identifiers, inheritance, phenotypes, variants, mechanisms, and key quantitative findings for the SRPX2-related speech-epilepsy-polymicrogyria spectrum. It is designed as a quick reference for integrating evidence from primary and recent review sources.
Primary and review sources used in this report are those retrieved in the current run and cited by context ID throughout (pqac-...). Key URLs include: * Roll et al., Human Molecular Genetics (Dec 2010): https://doi.org/10.1093/hmg/ddq415 (roll2010molecularnetworksimplicated pages 1-2) * Salmi et al., Brain (Aug 2013): https://doi.org/10.1093/brain/awt161 (salmi2013tubacinpreventsneuronal pages 1-2) * Bernardo et al., Int J Mol Sci (Apr 2024): https://doi.org/10.3390/ijms25074110 (bernardo2024xlinkedepilepsiesa pages 19-21) * James et al., Ann Indian Acad Neurol (Jul–Aug 2022): https://doi.org/10.4103/aian.aian_97_22 (james2022thegeneticlandscape pages 7-8) * Rudolf et al., Epilepsia (Aug 2009): https://doi.org/10.1111/j.1528-1167.2009.02214.x (rudolf2009fromrolandicepilepsy pages 1-2) * OpenTargets SRPX2 associations (accessed via tool): (OpenTargets Search: -SRPX2)
References
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(roll2010molecularnetworksimplicated pages 1-2): Patrice Roll, Sonja C. Vernes, Nadine Bruneau, Jennifer Cillario, Magali Ponsole-Lenfant, Annick Massacrier, Gabrielle Rudolf, Manal Khalife, Edouard Hirsch, Simon E. Fisher, and Pierre Szepetowski. Molecular networks implicated in speech-related disorders: foxp2 regulates the srpx2/upar complex. Human molecular genetics, 19 24:4848-60, Dec 2010. URL: https://doi.org/10.1093/hmg/ddq415, doi:10.1093/hmg/ddq415. This article has 132 citations and is from a domain leading peer-reviewed journal.
(salmi2013tubacinpreventsneuronal pages 1-2): Manal Salmi, Nadine Bruneau, Jennifer Cillario, Natalia Lozovaya, Annick Massacrier, Emmanuelle Buhler, Robin Cloarec, Timur Tsintsadze, Françoise Watrin, Vera Tsintsadze, Céline Zimmer, Claude Villard, Daniel Lafitte, Carlos Cardoso, Lan Bao, Gaetan Lesca, Gabrielle Rudolf, Françoise Muscatelli, Vanessa Pauly, Ilgam Khalilov, Pascale Durbec, Yehezkel Ben-Ari, Nail Burnashev, Alfonso Represa, and Pierre Szepetowski. Tubacin prevents neuronal migration defects and epileptic activity caused by rat srpx2 silencing in utero. Brain : a journal of neurology, 136 Pt 8:2457-73, Aug 2013. URL: https://doi.org/10.1093/brain/awt161, doi:10.1093/brain/awt161. This article has 66 citations.
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(royer2007molecularevolutionof pages 2-3): Barbara Royer, Dinesh C Soares, Paul N Barlow, Ronald E Bontrop, Patrice Roll, Andrée Robaglia-Schlupp, Antoine Blancher, Anthony Levasseur, Pierre Cau, Pierre Pontarotti, and Pierre Szepetowski. Molecular evolution of the human srpx2 gene that causes brain disorders of the rolandic and sylvian speech areas. BMC Genetics, 8:72-72, Oct 2007. URL: https://doi.org/10.1186/1471-2156-8-72, doi:10.1186/1471-2156-8-72. This article has 36 citations.
(salmi2013tubacinpreventsneuronal pages 2-2): Manal Salmi, Nadine Bruneau, Jennifer Cillario, Natalia Lozovaya, Annick Massacrier, Emmanuelle Buhler, Robin Cloarec, Timur Tsintsadze, Françoise Watrin, Vera Tsintsadze, Céline Zimmer, Claude Villard, Daniel Lafitte, Carlos Cardoso, Lan Bao, Gaetan Lesca, Gabrielle Rudolf, Françoise Muscatelli, Vanessa Pauly, Ilgam Khalilov, Pascale Durbec, Yehezkel Ben-Ari, Nail Burnashev, Alfonso Represa, and Pierre Szepetowski. Tubacin prevents neuronal migration defects and epileptic activity caused by rat srpx2 silencing in utero. Brain : a journal of neurology, 136 Pt 8:2457-73, Aug 2013. URL: https://doi.org/10.1093/brain/awt161, doi:10.1093/brain/awt161. This article has 66 citations.
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