Pathological ASXL1 Mutations and Protein Variants Impair Neural Crest Development
Friederike Matheus1, Ejona Rusha2, Rizwan Rehimi3
1Institute for Stem Cell Research, Helmholtz Zentrum München GmbH, 85764 Neuherberg, Germany.
Stem Cell Reports
|April 23, 2019
Summary
Mutations in ASXL1 disrupt neural crest (NC) development, causing impaired cell delamination and emigration. This study reveals how ASXL1 variants contribute to Bohring-Opitz syndrome (BOS) pathology.
Area of Science:
- Developmental Biology
- Genetics
- Stem Cell Biology
Background:
- Neural crest (NC) cells are crucial for fetal tissue development.
- Misregulation of NC development is linked to congenital malformations.
- Bohring-Opitz syndrome (BOS) is associated with mutations in the ASXL1 gene.
Purpose of the Study:
- To investigate the molecular mechanisms of NC-related symptoms in BOS.
- To understand the role of ASXL1 mutations in NC development.
Main Methods:
- Genetically edited human pluripotent stem cells differentiated to NC progenitors.
- Xenotransplantation into chicken embryos.
- Molecular analysis of gene expression and protein activity.
- Induced pluripotent stem cell lines from BOS patients.
Main Results:
- ASXL1 mutations impaired NC delamination and emigration in vivo.
- Reduced activation of ZIC1 and the NC gene regulatory network was observed.
- Truncated ASXL1 isoforms recapitulated NC phenotypes in vitro and in ovo.
Conclusions:
- ASXL1 mutations disrupt human neural crest development.
- Truncated ASXL1 variants may contribute to Bohring-Opitz syndrome pathology.
- This study enhances understanding of ASXL1's role in NC development and BOS.
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