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Thues C, Valadas JS, Deaulmerie L, et al. MAPRE2 mutations result in altered human cranial neural crest migration, underlying craniofacial malformations in CSC-KT syndrome. Sci Rep. 2021;11(1):4976doi: 10.1038/s41598-021-83771-3.
Thues, C., Valadas, J. S., Deaulmerie, L., Geens, A., Chouhan, A. K., Duran-Romaña, R., Schymkowitz, J., Rousseau, F., Bartusel, M., Rehimi, R., Rada-Iglesias, A., Verstreken, P., & Van Esch, H. (2021). MAPRE2 mutations result in altered human cranial neural crest migration, underlying craniofacial malformations in CSC-KT syndrome. Scientific reports, 11(1), 4976. https://doi.org/10.1038/s41598-021-83771-3
Thues, Cedric, et al. "MAPRE2 mutations result in altered human cranial neural crest migration, underlying craniofacial malformations in CSC-KT syndrome." Scientific reports vol. 11,1 (2021): 4976. doi: https://doi.org/10.1038/s41598-021-83771-3
Thues C, Valadas JS, Deaulmerie L, Geens A, Chouhan AK, Duran-Romaña R, Schymkowitz J, Rousseau F, Bartusel M, Rehimi R, Rada-Iglesias A, Verstreken P, Van Esch H. MAPRE2 mutations result in altered human cranial neural crest migration, underlying craniofacial malformations in CSC-KT syndrome. Sci Rep. 2021 Mar 02;11(1):4976. doi: 10.1038/s41598-021-83771-3. PMID: 33654163; PMCID: PMC7925611.
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Sci Rep. 2021 Mar 02;11(1):4976. doi: 10.1038/s41598-021-83771-3.

MAPRE2 mutations result in altered human cranial neural crest migration, underlying craniofacial malformations in CSC-KT syndrome.

Scientific reports

Cedric Thues, Jorge S Valadas, Liesbeth Deaulmerie, Ann Geens, Amit K Chouhan, Ramon Duran-Romaña, Joost Schymkowitz, Frederic Rousseau, Michaela Bartusel, Rizwan Rehimi, Alvaro Rada-Iglesias, Patrik Verstreken, Hilde Van Esch

Affiliations

  1. Laboratory for the Genetics of Cognition, Department of Human Genetics, Center for Human Genetics, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
  2. VIB Center for Brain & Disease Research, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
  3. Department of Neurosciences, Leuven Brain Institute, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
  4. Switch Laboratory, VIB Center for Brain and Disease Research, Herestraat 49, 3000, Leuven, Belgium.
  5. Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
  6. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Strasse 21, 50931, Cologne, Germany.
  7. Department of Biology, Massachusetts Institute of Technology, 31 Ames St., Cambridge, MA, 02142, USA.
  8. Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931, Cologne, Germany.
  9. Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), CSIC/Universidad de Cantabria, Albert Einstein 22, 39011, Santander, Spain.
  10. Laboratory for the Genetics of Cognition, Department of Human Genetics, Center for Human Genetics, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. [email protected].

PMID: 33654163 PMCID: PMC7925611 DOI: 10.1038/s41598-021-83771-3

Abstract

Circumferential skin creases (CSC-KT) is a rare polymalformative syndrome characterised by intellectual disability associated with skin creases on the limbs, and very characteristic craniofacial malformations. Previously, heterozygous and homozygous mutations in MAPRE2 were found to be causal for this disease. MAPRE2 encodes for a member of evolutionary conserved microtubule plus end tracking proteins, the end binding (EB) family. Unlike MAPRE1 and MAPRE3, MAPRE2 is not required for the persistent growth and stabilization of microtubules, but plays a role in other cellular processes such as mitotic progression and regulation of cell adhesion. The mutations identified in MAPRE2 all reside within the calponin homology domain, responsible to track and interact with the plus-end tip of growing microtubules, and previous data showed that altered dosage of MAPRE2 resulted in abnormal branchial arch patterning in zebrafish. In this study, we developed patient derived induced pluripotent stem cell lines for MAPRE2, together with isogenic controls, using CRISPR/Cas9 technology, and differentiated them towards neural crest cells with cranial identity. We show that changes in MAPRE2 lead to alterations in neural crest migration in vitro but also in vivo, following xenotransplantation of neural crest progenitors into developing chicken embryos. In addition, we provide evidence that changes in focal adhesion might underlie the altered cell motility of the MAPRE2 mutant cranial neural crest cells. Our data provide evidence that MAPRE2 is involved in cellular migration of cranial neural crest and offers critical insights into the mechanism underlying the craniofacial dysmorphisms and cleft palate present in CSC-KT patients. This adds the CSC-KT disorder to the growing list of neurocristopathies.

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