CRMP1 Human

What is the molecular structure of CRMP1 and how does it function in neural development?

CRMP1 is a cytosolic phosphoprotein that exists in two isoforms due to alternative splicing: CRMP1A (686 amino acids, long form) and CRMP1B (572 amino acids, short form). CRMP1B represents the major isoform expressed in the nervous system and has been the focus of most structural studies . X-ray crystallography at 3.05 Å resolution reveals that a CRMP1 monomer consists of three structural components: N-terminal β-strands, a connecting linker β-strand, and a central α/β-barrel . This structural analysis lacks the N-terminal 14 residues and residues 491-572 in the C-terminal region, indicating potential flexibility in these regions.

CRMP1 plays essential roles in multiple neurodevelopmental processes including cell migration, axonal outgrowth, dendritic branching, and apoptosis. These functions are regulated through interactions with extracellular signaling molecules such as Sema3A, reelin, and neurotrophins . The protein's activity is controlled by spatiotemporal phosphorylation patterns mediated by various kinases including Cdk5, Rho/ROCK, and GSK3 . This phosphorylation-dependent regulation allows CRMP1 to coordinate different aspects of neuronal development at specific developmental stages and in distinct neuronal populations.

Functionally, knockout studies in mice have demonstrated that Crmp1 deficiency results in impaired learning and memory, schizophrenia-associated behaviors, and prepulse inhibition deficits . At the cellular level, these models exhibit abnormal neurite outgrowth, altered dendritic development and orientation, and impaired spine maturation in cortical and hippocampal neurons .

How does CRMP1 oligomerization contribute to its biological function?

CRMP1 forms homo-tetramers and hetero-tetramers with other CRMP family members (CRMP1-5), creating diverse functional complexes critical for neurodevelopment . The quaternary structure of CRMP1 tetramers depends on specific amino acids at the oligomerization interface. Structural analysis has identified several highly conserved residues, including P475, T313, and F237, that contribute significantly to the oligomerization properties of the protein .

This oligomerization capability is functionally significant, as it enables CRMP1 to participate in different protein complexes with distinct functions. The ability to form various combinatorial tetramers with other CRMP proteins provides versatility in function and regulation across different neuronal populations and developmental stages. Recent research on pathogenic CRMP1 variants demonstrates that disruption of this oligomerization process can have profound effects on neuronal development .

Experimental evidence shows that variants such as P475L and T313M significantly affect homo-oligomerization of CRMP1B . This disruption likely alters the protein's ability to form functional complexes, thereby affecting downstream signaling pathways and cellular processes such as neurite outgrowth . The oligomerization state of CRMP1 may also influence its interactions with other cellular components, including cytoskeletal elements that are critical for neuronal morphogenesis.

What transcriptional and post-translational mechanisms regulate CRMP1 activity?

CRMP1 activity is regulated through multiple mechanisms that ensure its proper function in neurodevelopment. At the transcriptional level, CRMP1 expression is dynamically regulated throughout development, with differential expression patterns in various regions of the nervous system . Alternative splicing generates the two main isoforms (CRMP1A and CRMP1B), with CRMP1B serving as the predominant form in the nervous system .

Post-translationally, phosphorylation represents a primary regulatory mechanism for CRMP1 function. Several kinases, including Cdk5, Rho/ROCK, and GSK3, phosphorylate CRMP1 at specific residues, modulating its activity, localization, and interactions with binding partners . This phosphorylation-dependent regulation is crucial for CRMP1's role in processes such as growth cone dynamics and neurite outgrowth.

Protein-protein interactions provide another layer of regulation. Beyond oligomerization with other CRMP family members, CRMP1 interacts with various signaling molecules and cytoskeletal components. These interactions are often regulated by the phosphorylation state of CRMP1, creating a complex regulatory network that integrates multiple signaling pathways.

Altered regulation of CRMP1 has been observed in several neuropsychiatric conditions. Increased CRMP1 mRNA levels have been identified in individuals with schizophrenia, attention-deficit hyperactivity disorder, and autism spectrum disorder (ASD) . Additionally, maternal CRMP1 autoantibodies have been associated with autism in offspring, suggesting that disruption of normal CRMP1 function can contribute to neurodevelopmental disorders through various mechanisms .

What types of CRMP1 variants have been identified in neurodevelopmental disorders?

Recent research has identified heterozygous de novo variants in the CRMP1 gene in three unrelated individuals with neurodevelopmental disorders . These variants include:

• c.1766C>T (p.P589L in CRMP1A/p.P475L in CRMP1B) - Identified in Proband 1

• c.1280C>T (p.T427M in CRMP1A/p.T313M in CRMP1B) - Identified in Proband 2

• c.1052T>C (p.F351S in CRMP1A/p.F237S in CRMP1B) - Identified in Proband 3

All three variants occur at highly conserved positions within the CRMP1 protein, with the P589L variant showing a PhyloP score of 5.327 and PhastCons score of 1, indicating exceptional evolutionary conservation . In silico analysis predicts these variants to be deleterious, with the P589L variant having a CADD phred score of 24.8 and REVEL score of 0.695 .

These variants are distributed across different domains of the protein, but all appear to affect regions important for protein structure and/or function. Notably, none of these variants have been found in population databases such as 1000Genomes, dbSNP, or gnomAD, further supporting their pathogenicity . The de novo occurrence of these variants in unrelated individuals with similar phenotypes provides strong evidence for their causative role in the observed neurodevelopmental disorders.

Functional studies have demonstrated that at least two of these variants (P475L and T313M in the CRMP1B isoform) significantly impact CRMP1 oligomerization , providing a molecular mechanism for their pathogenicity. This represents the first direct link between genetic variants in CRMP1 and human neurodevelopmental disorders.

What are the clinical phenotypes associated with pathogenic CRMP1 variants?

The clinical phenotypes associated with pathogenic CRMP1 variants encompass a spectrum of neurodevelopmental features with both shared and distinct manifestations across affected individuals. All three reported probands exhibited:

• Moderate intellectual disability

• Delayed speech and language development (first words at 24-36 months)

• Behavioral problems

• Normal electroencephalogram (EEG) results and cranial MRI findings

A comprehensive overview of clinical features is presented in the following table:

Proband 1 presented with slurred speech, generalized muscular hypotonia, fine motor problems, and a broad-based gait without ataxia . Proband 3 developed severe behavioral issues including temper tantrums, stubbornness, hyperphagia, obsessive-compulsive characteristics, and ASD . Metabolic testing in this patient revealed normal results despite severe obesity.

How do pathogenic CRMP1 variants disrupt normal protein function?

Pathogenic CRMP1 variants disrupt normal protein function through several molecular mechanisms:

• Impaired protein oligomerization: Functional studies have demonstrated that variants such as P475L and T313M significantly affect the homo-oligomerization of CRMP1B . Since CRMP1 typically forms homo-tetramers and hetero-tetramers with other CRMP family members, disruption of this oligomerization process likely impairs the formation of functional protein complexes necessary for proper neuronal development.

• Structural alterations: In silico analysis predicts that the identified variants affect CRMP1 structure . The affected amino acids (P475/P589, T313/T427, and F237/F351) are located in highly conserved regions of the protein that contribute to its structural integrity and functional properties . The P589L variant, for example, affects a proline residue, which often plays critical roles in protein folding and structure.

• Altered neurite outgrowth: Overexpression of CRMP1 variants affects neurite outgrowth in murine cortical neurons . This finding directly links the genetic variants to disruption of a critical neurodevelopmental process, providing a cellular mechanism for the observed clinical phenotypes.

• Potential dominant-negative effects: The pattern of inheritance (heterozygous de novo variants) and functional studies suggest that these variants might exert dominant-negative effects rather than simple haploinsufficiency . By incorporating mutant CRMP1 proteins into oligomeric complexes, they could potentially disrupt the function of wild-type proteins as well.

The precise balance between loss-of-function and dominant-negative mechanisms remains under investigation. Reviewer comments indicate that "clarification of the disease mechanism is needed for therapeutic considerations," highlighting the importance of determining whether "gene augmentation therapies might rescue the phenotype (loss-of-function/haploinsufficiency) or if allele-specific knockdown or gene editing is necessary (dominant negative)" .

What methodologies are most effective for analyzing CRMP1 oligomerization?

Several complementary methodologies have proven effective for analyzing CRMP1 oligomerization:

• Recombinant protein purification and characterization: The production of purified recombinant human CRMP1B (wild-type and variant forms) provides the foundation for detailed structural and functional studies . This approach allows for controlled analysis of protein properties in isolation from the cellular environment.

• Size exclusion chromatography: This technique separates proteins based on their molecular size, allowing researchers to analyze the oligomeric states of CRMP1 proteins . Size exclusion chromatography has been particularly valuable for comparing wild-type and variant CRMP1 proteins, revealing differences in their ability to form tetramers. Reviewers specifically highlighted the importance of this technique, requesting additional experimental details in revised manuscripts .

• Structural biology approaches: X-ray crystallography has been successfully employed to determine the structure of CRMP1B at 3.05 Å resolution, providing insights into the oligomerization interface . This structural information is crucial for understanding how specific variants might disrupt oligomerization.

• Computational structural analysis: Protein structure prediction tools offer complementary approaches for modeling the effects of variants on CRMP1 structure and oligomerization. These computational methods can provide insights even for regions not resolved in crystal structures, such as the C-terminal domain.

• Biochemical cross-linking: Chemical cross-linking followed by mass spectrometry or gel electrophoresis can identify specific residues involved in oligomerization and determine how variants affect these interactions.

• Co-immunoprecipitation assays: These assays can assess interactions between different CRMP family members and determine how variants impact the formation of hetero-oligomers.

A comprehensive approach combining multiple methodologies provides the most robust characterization of CRMP1 oligomerization and how it is affected by disease-associated variants. The combination of structural, biochemical, and computational approaches has been particularly effective in elucidating the molecular mechanisms underlying CRMP1-related disorders .

What cellular models best capture the impact of CRMP1 variants on neuronal development?

Several cellular models have proven valuable for investigating the impact of CRMP1 variants on neuronal development:

• Primary cortical neurons: Murine primary cortical neurons have been successfully used to assess the effects of CRMP1 variants on neurite outgrowth . This system provides a physiologically relevant context for studying CRMP1 function in neurodevelopment, as it utilizes neurons from a brain region where CRMP1 plays important roles.

• Hippocampal neurons: Given the role of CRMP1 in hippocampal neuron development and function, primary hippocampal cultures represent another valuable model system. These neurons exhibit well-characterized developmental stages and morphological features that can be quantitatively assessed.

• Neuronal cell lines: Immortalized neuronal cell lines (such as SH-SY5Y, Neuro2A, or PC12 cells) that can be differentiated into neuron-like cells provide more accessible systems for initial screening and mechanistic studies.

• Patient-derived iPSCs: While not explicitly mentioned in the search results, patient-derived induced pluripotent stem cells (iPSCs) differentiated into relevant neural cell types would provide a human-specific context for studying the effects of CRMP1 variants. This approach maintains the patient's genetic background, which may influence the manifestation of CRMP1 variants.

• CRISPR-engineered isogenic lines: The generation of isogenic cell lines with specific CRMP1 variants introduced via CRISPR/Cas9 gene editing offers a controlled system for variant comparison. This approach eliminates the confounding effects of different genetic backgrounds.

For optimal characterization of CRMP1 variant effects, researchers should consider several analytical approaches:

• Detailed morphometric analysis of neuronal development (neurite length, branching, growth cone dynamics)

• Time-lapse imaging to capture dynamic aspects of neuronal development

• Protein localization studies to assess whether variants affect CRMP1 distribution

• Molecular interaction studies to determine effects on binding partners

• Phosphorylation analysis, given CRMP1's regulation by various kinases

The reviewers specifically recommended analyzing gene expression abundance of CRMP1 in heterozygous variant carriers and non-carriers when possible, indicating the value of expression analysis in understanding variant impact .

How can animal models be optimized for studying CRMP1-related neurodevelopmental disorders?

Optimizing animal models for studying CRMP1-related neurodevelopmental disorders requires careful consideration of several factors:

• Model selection based on research objectives: Different animal models offer distinct advantages depending on the specific research questions:

  • Mouse models provide mammalian neurodevelopmental processes most similar to humans

  • Zebrafish offer advantages for high-throughput screening and live imaging

  • Drosophila and C. elegans can provide insights into fundamental aspects of CRMP function

• Genetic strategy optimization:

  • Crmp1 knockout mice: Existing Crmp1 knockout mice exhibit relevant phenotypes including schizophrenia-associated behavior, impaired learning and memory, and abnormal neurite outgrowth . These models are valuable for understanding loss-of-function effects.

  • Knock-in models of human variants: Generation of mice carrying specific human variants (P589L, T427M, F351S) would allow direct assessment of their effects in vivo and potential genotype-phenotype correlations.

  • Conditional models: Given CRMP1's broad expression, conditional models allowing temporal and spatial control of gene modification would help dissect region-specific functions.

• Comprehensive phenotyping approaches:

  • Behavioral assessment: Standardized tests evaluating cognitive function, social behavior, motor coordination, and other relevant domains

  • Electrophysiological studies: To assess potential alterations in neuronal activity and network function

  • Detailed morphological analysis: Examination of neuronal development in relevant brain regions

  • Molecular and biochemical analyses: Assessment of CRMP1 expression, oligomerization, and interactions in vivo

• Developmental considerations:

  • Assessment across multiple developmental timepoints to capture the dynamic nature of CRMP1's role in neurodevelopment

  • Correlation of developmental processes in model organisms with human developmental stages

• Translational relevance:

  • Validation of findings across multiple model systems

  • Direct comparison with human patient data when available

  • Focus on phenotypes relevant to the human condition (intellectual disability, motor issues, behavioral problems)

Mouse models have already provided valuable insights into CRMP1 function, with Crmp1 knockout mice showing abnormal neurite outgrowth, dendritic development, and spine maturation in cortical and hippocampal neurons . These phenotypes partially overlap with human CRMP1-related disorders, supporting the validity of mouse models for studying these conditions.

How can researchers distinguish between loss-of-function and dominant-negative effects of CRMP1 variants?

Distinguishing between loss-of-function and dominant-negative effects of CRMP1 variants requires a multi-faceted experimental approach:

• Quantitative expression analysis:

  • Compare expression levels of wild-type and variant CRMP1 using qRT-PCR and western blotting

  • Assess mRNA stability and protein half-life through pulse-chase experiments

  • Examine whether variants affect the expression of the wild-type allele in heterozygous systems

• Functional rescue experiments:

  • In cellular models exhibiting phenotypes due to variant expression, test whether increasing wild-type CRMP1 can rescue the phenotype (suggesting dominant-negative effects)

  • Alternatively, assess whether reducing total CRMP1 levels worsens or improves the phenotype (helping differentiate gain-of-function from loss-of-function)

  • Systematically vary the ratio of wild-type to variant CRMP1 to establish dose-response relationships

• Structural and biochemical characterization:

  • Determine whether variants completely abolish protein function or create altered functionality

  • Assess if variant proteins can incorporate into oligomers with wild-type proteins

  • Characterize the composition and function of mixed oligomers containing both wild-type and variant proteins

• Comparative phenotyping:

  • Compare phenotypes of variant expression with those of CRMP1 knockdown/knockout

  • Assess whether variants produce effects beyond simple loss-of-function

  • Examine phenotypes in heterozygous versus homozygous model systems

• In vivo analysis in animal models:

  • Compare heterozygous knockout models with heterozygous knock-in models of specific variants

  • Utilize tissue-specific or inducible expression systems to examine spatial and temporal requirements

This comprehensive approach is critical for therapeutic development, as reviewer comments emphasize: "clarification of the disease mechanism is needed for therapeutic considerations, i.e., whether gene augmentation therapies might rescue the phenotype (loss-of-function/haploinsufficiency) or if allele-specific knockdown or gene editing is necessary (dominant negative)" . Determining the precise disease mechanism will direct the development of appropriate therapeutic strategies for CRMP1-related disorders.

What are the regulatory networks governing CRMP1 expression during neurodevelopment?

The regulatory networks governing CRMP1 expression during neurodevelopment involve complex interactions between transcriptional regulators, signaling pathways, and post-transcriptional mechanisms:

Understanding these regulatory networks is crucial for developing therapeutic strategies targeting CRMP1 expression or function. Future research should focus on mapping the complete regulatory landscape controlling CRMP1 expression throughout neurodevelopment, potentially identifying nodes that could be targeted for therapeutic intervention in CRMP1-related disorders.

How do CRMP1 interactions with cytoskeletal elements mediate neurodevelopmental processes?

CRMP1 interactions with cytoskeletal elements are fundamental to its role in mediating key neurodevelopmental processes:

• Growth cone dynamics and axon guidance:

  • CRMP1 functions as a downstream mediator of Sema3A signaling, which regulates growth cone collapse and axon guidance

  • This function involves CRMP1's interactions with actin and microtubule cytoskeletal elements

  • Phosphorylation of CRMP1 by kinases such as Cdk5, Rho/ROCK, and GSK3 modulates these interactions, translating extracellular guidance cues into cytoskeletal rearrangements

• Neurite outgrowth regulation:

  • Experimental evidence shows that CRMP1 variants affect neurite outgrowth of murine cortical neurons

  • CRMP1 promotes microtubule assembly and stability, crucial processes for neurite extension

  • The protein likely serves as a molecular bridge between signaling pathways and the cytoskeletal machinery driving neurite outgrowth

• Dendritic development and arborization:

  • Studies in Crmp1 knockout mice reveal abnormal dendritic development and orientation

  • CRMP1 may regulate the differential dynamics of cytoskeletal elements in dendrites versus axons

  • Its interaction with the cytoskeleton contributes to the establishment of neuronal polarity and appropriate dendritic field development

• Spine formation and maturation:

  • Crmp1 knockout mice exhibit abnormalities in spine maturation

  • CRMP1 likely influences the actin-rich structures that form the foundation of dendritic spines

  • Local regulation of CRMP1 activity through phosphorylation may contribute to activity-dependent spine remodeling

• Mechanistic model of CRMP1 variants:

  • The identified CRMP1 variants that cause neurodevelopmental disorders disrupt protein oligomerization

  • This oligomerization is likely critical for proper interaction with cytoskeletal elements

  • Disrupted oligomerization may prevent CRMP1 from effectively organizing cytoskeletal components during critical neurodevelopmental processes

The cytoskeletal interactions of CRMP1 represent a mechanistic link between genetic variations and the cellular phenotypes observed in neurodevelopmental disorders. Advanced imaging techniques, such as super-resolution microscopy and live cell imaging, would be valuable for further elucidating how CRMP1 variants affect cytoskeletal dynamics in developing neurons.

What diagnostic approaches are most effective for identifying CRMP1-related disorders?

Effective diagnosis of CRMP1-related disorders requires a comprehensive approach combining clinical evaluation, genetic testing, and functional validation:

• Clinical recognition of core features:

  • Intellectual disability (moderate in all reported cases)

  • Delayed speech and language development (first words at 24-36 months)

  • Muscular hypotonia

  • Behavioral problems

  • Normal EEG results and normal cranial MRI findings

  • Variable features may include hyperphagia, obesity, and autism spectrum disorder features

• Genetic testing strategies:

  • Whole exome sequencing (WES): This approach successfully identified CRMP1 variants in the reported cases . Appropriate quality control measures are essential, with reviewers specifically requesting "more details on the QC values of WES (percent of exome captured, percent of exome analyzed, depth of coverage, etc.)"

  • Trio analysis: Testing affected individuals and both parents to identify de novo variants

  • Variant confirmation: Sanger sequencing to verify variants identified through next-generation sequencing methods

  • Copy number variant (CNV) analysis: As recommended by reviewers, details on CNV analysis (SNP-array, WES-based CNV analysis) should be included in the diagnostic workup

• Variant interpretation:

  • In silico prediction tools: Utilization of tools such as CADD, REVEL, PhyloP, and PhastCons to assess variant pathogenicity

  • Population databases: Checking variant frequency in databases such as 1000Genomes, dbSNP, and gnomAD

  • Conservation analysis: Multi-species sequence alignment to evaluate evolutionary conservation of affected residues

• Functional validation:

  • When possible, functional studies to assess the impact of identified variants on protein structure and function

  • Laboratory investigations to rule out other causes, including metabolic and endocrinological surveys particularly for patients with obesity

• Interdisciplinary assessment:

  • Neurological evaluation

  • Developmental assessment

  • Behavioral/psychiatric evaluation

  • Speech and language assessment

  • Physical therapy assessment

As more patients with CRMP1 variants are identified, the phenotypic spectrum will likely expand, potentially requiring refinement of diagnostic criteria. Researchers should maintain detailed clinical databases of identified patients to facilitate genotype-phenotype correlations and improve diagnostic accuracy.

What therapeutic strategies show promise for CRMP1-related neurodevelopmental disorders?

Several therapeutic strategies show potential for CRMP1-related neurodevelopmental disorders, though all remain in early developmental stages:

• Gene-based approaches:

  • Gene augmentation therapy: If CRMP1 variants act through haploinsufficiency or loss-of-function mechanisms, providing additional copies of wild-type CRMP1 could potentially compensate for reduced function

  • Allele-specific silencing: For dominant-negative variants, selectively suppressing expression of the mutant allele while preserving wild-type expression could be beneficial

  • CRISPR-based gene editing: Correction of specific variants represents a potential curative approach, though significant challenges remain for clinical implementation

• Protein-targeted approaches:

  • Small molecule stabilizers: Compounds that promote proper CRMP1 oligomerization could potentially counteract the effects of variants that disrupt this process

  • Targeting post-translational modifications: Modulating the phosphorylation status of CRMP1 through kinase inhibitors might compensate for dysfunction caused by certain variants

• Pathway-based interventions:

  • Modulation of downstream effectors: Identifying and targeting the downstream pathways affected by CRMP1 dysfunction

  • Targeting upstream regulators: Modifying the activity of pathways that regulate CRMP1 expression or function

• Symptom-specific interventions:

  • Behavioral therapies: For the behavioral issues present in all reported cases

  • Speech and language therapy: For the delayed speech and language development common to all cases

  • Physical and occupational therapy: For muscular hypotonia and fine motor problems

  • Nutritional and endocrine management: For obesity and hyperphagia present in some cases

Developing effective therapeutics requires further clarification of disease mechanisms. As reviewers noted, determining whether variants act through loss-of-function/haploinsufficiency or dominant-negative mechanisms is critical for selecting appropriate therapeutic strategies . Early intervention across multiple domains (cognitive, behavioral, motor) remains important for maximizing developmental potential while targeted therapeutics are developed.

How might understanding CRMP1 pathways inform broader neurodevelopmental disorder research?

Understanding CRMP1 pathways has significant potential to inform broader neurodevelopmental disorder research:

• Insights into shared molecular mechanisms:

  • CRMP1 functions in fundamental neurodevelopmental processes including cell migration, axonal outgrowth, dendritic branching, and apoptosis

  • These processes are disrupted in many neurodevelopmental disorders, suggesting common pathogenic mechanisms

  • CRMP1's regulation by kinases like Cdk5, Rho/ROCK, and GSK3 links it to signaling pathways implicated in multiple neurodevelopmental conditions

• CRMP family insights and therapeutic targets:

  • Other CRMP family members have been linked to neurodevelopmental disorders: CRMP5 variants cause Ritscher–Schinzel syndrome 4, and CRMP4 variants are associated with amyotrophic lateral sclerosis

  • Comparative analysis of different CRMP proteins could reveal common therapeutic targets within this protein family

  • The ability of CRMPs to form various homo- and hetero-tetramers suggests complex regulatory networks that might be relevant to multiple disorders

• Model for genotype-phenotype correlations:

  • The three identified CRMP1 variants show both shared and distinct clinical manifestations

  • This variable expressivity provides a model for studying how specific genetic variants translate to phenotypic diversity

  • Understanding these correlations could help explain the heterogeneity observed in many neurodevelopmental disorders

• Connecting cellular phenotypes to clinical presentations:

  • CRMP1 research directly links molecular dysfunction (disrupted oligomerization) to cellular phenotypes (altered neurite outgrowth) and clinical manifestations (intellectual disability, hypotonia)

  • This multilevel approach provides a template for investigating other neurodevelopmental disorder genes

• Understanding developmental comorbidities:

  • The varied phenotypes associated with CRMP1 variants (intellectual disability, ASD, hypotonia, behavioral issues) reflect common comorbidities in neurodevelopmental disorders

  • CRMP1 research may help explain why certain developmental processes are commonly affected together

• Translational implications:

  • Insights from CRMP1 research could inform therapeutic strategies for other neurodevelopmental disorders

  • Understanding whether interventions need to target gene expression, protein function, or downstream pathways will have broad applicability

  • The timing and specificity requirements for effective intervention may provide generalizable principles for neurodevelopmental disorder treatment

By elucidating these aspects of CRMP1 biology and pathology, researchers can contribute to a more comprehensive understanding of neurodevelopmental disorders, potentially leading to novel diagnostic and therapeutic approaches for a range of conditions beyond CRMP1-related disorders.