Monoallelic CRMP1 gene variants cause neurodevelopmental disorder

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    Evaluation Summary:

    This manuscript describes de novo dominant toxic mutations in CRMP1 in 3 probands with a shared neurodevelopmental phenotype. The authors show that the mutations lead to reduced protein production from recombinant expression and that the mutations correlate with shorter neurites in cultured cells. This is the first report of mutations in CRMP1 in humans, encoding a cytoskeletal regulator protein. The results could have implications for physicians, geneticists, neurodevelopmental scientists, and cell biologists.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

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Abstract

Collapsin response mediator proteins (CRMPs) are key for brain development and function. Here, we link CRMP1 to a neurodevelopmental disorder. We report heterozygous de novo variants in the CRMP1 gene in three unrelated individuals with muscular hypotonia, intellectual disability, and/or autism spectrum disorder. Based on in silico analysis these variants are predicted to affect the CRMP1 structure. We further analyzed the effect of the variants on the protein structure/levels and cellular processes. We showed that the human CRMP1 variants impact the oligomerization of CRMP1 proteins. Moreover, overexpression of the CRMP1 variants affect neurite outgrowth of murine cortical neurons. While altered CRMP1 levels have been reported in psychiatric diseases, genetic variants in CRMP1 gene have never been linked to human disease. We report for the first-time variants in the CRMP1 gene and emphasize its key role in brain development and function by linking directly to a human neurodevelopmental disease.

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  1. Author Response

    Reviewer #1 (Public Review):

    1. In family 2, the variant was detected by routine trio-based WES diagnostics. Sanger confirmation was not performed. IGV images can be added as supplementary material. Furthermore, median coverage was 75× which might not be sufficient for the identification of all heterozygous variants.

    We thank reviewer for pointing it out for clarification. Obviously, at the time (2016) of the reporting of this variant this was our laboratory’s thoroughly validated protocol, which shows that median (!) coverage of 75x with the technology at the time is more than sufficient for robust variant calling. This particular variant was actually below 75X in coverage (at 65x), but Sanger confirmation was not necessary (based on thorough validation of the robustness of calling and GATK scores and other quality …

  2. Evaluation Summary:

    This manuscript describes de novo dominant toxic mutations in CRMP1 in 3 probands with a shared neurodevelopmental phenotype. The authors show that the mutations lead to reduced protein production from recombinant expression and that the mutations correlate with shorter neurites in cultured cells. This is the first report of mutations in CRMP1 in humans, encoding a cytoskeletal regulator protein. The results could have implications for physicians, geneticists, neurodevelopmental scientists, and cell biologists.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

  3. Reviewer #1 (Public Review):

    In this study, Ravindran et al. describe heterozygous de novo variants in the CRMP1 gene in three unrelated kindreds with muscular hypotonia, autism spectrum disorder, and/or intellectual disability. Based on in silico analysis these variants are predicted to affect the CRMP1 structure. The effect of these variants on the protein structure/levels and cellular processes was analyzed. The authors show that the identified CRMP1 variants are dominant-negative and impact the oligomerization of CRMP1 proteins. Moreover, overexpression of mutant-CRMP1 variants affects neurite outgrowth of murine cortical neurons. It has been known that maternal autoantibody reactivity to CRMP1 significantly increases the odds of a child having a higher Autism Diagnostic Observation Schedule (ADOS) severity score (PMID: 33483694), …

  4. Reviewer #2 (Public Review):

    In "Monoallelic CRMP1 gene variants cause neurodevelopmental disorder," Ravindran et al. attempt to demonstrate that de novo variation in CRMP1, the gene encoding collapsing response mediator protein 1, causes human neurodevelopmental disorders by disrupting CRMP1 oligomerization and neurite outgrowth.

    The major strengths of the article include:

    - Strong genomic data. The identification of de novo, ultra-rare, predicted damaging missense CRMP1 missense variants in three probands with neurodevelopmental disorders is compelling evidence of a novel disease-gene association.

    - Thorough phenotypic characterization of all subjects demonstrating a non-syndromic neurodevelopmental disorder characterized by developmental delay, behavioral abnormalities, intellectual disability, and autism.

    - Strong functional data …

  5. Reviewer #3 (Public Review):

    This manuscript identifies specific dominant-negative mutations in the CRMP1 gene encoding Collapsing response mediator protein 1 involved in cytoskeletal remodeling. The authors identified 3 independent probands, each with a de novo CRMP1 mutation-based upon unbiased exome or genome sequencing. Family 1 showed p.P589L/p.P475L, family 2 showed p.T427M/p.T313M and family 3 showed p.A351S/p.A237S. CRIMP1 is known to homo-oligomerize, and the paper attempts to show defects in this ability with the incorporation of patient mutations. Finally, forced expression of patient mutations into neuronal cells show defects in the length of the longest neurite.

    Major weakness:

    The major weakness is Figure 2, as it is not performed up to high standards like the rest of the paper. Panel A does not show any loading control …