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A loss-of-function mutation in the CFC domain of TDGF1 is associated with human forebrain defects
June M de la Cruz1, Richard N Bamford, Rebecca D Burdine
1Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, 10 Center Drive, MSC 1852, Building 10 Room 10C103, Bethesda, MD 20892-1852, USA.
Abstract:
TDGF1 (CRIPTO) is an EGF-CFC family member and an obligate co-receptor involved in NODAL signaling, a developmental program implicated in midline, forebrain, and left-right axis development in model organisms. Previous studies of CFC1 (CRYPTIC), another member of the EGF-CFC family, demonstrated that normal function of this protein is required for proper laterality development in humans. Here we identify a mutation in the conserved CFC domain of TDGF1 in a patient with midline anomalies of the forebrain. The mutant protein is inactive in a zebrafish rescue assay, indicating a role for TDGF1 in human midline and forebrain development.
Insights
Tissue Differentiation Factor 1 (TDGF1) mutations can cause midline and forebrain developmental anomalies in humans. A patient mutation rendered the TDGF1 protein inactive, confirming its critical role in human development.
Area of Science:
- Developmental Biology
- Human Genetics
- Molecular Biology
Background:
- TDGF1 (CRIPTO) is an EGF-CFC protein crucial for NODAL signaling.
- NODAL signaling is vital for embryonic development, including axis formation.
- Previous research linked CFC1 (CRYPTIC) to human laterality development.
Purpose of the Study:
- To investigate the role of TDGF1 in human midline and forebrain development.
- To identify mutations in TDGF1 associated with developmental anomalies.
Main Methods:
- Genetic analysis to identify mutations in TDGF1.
- Functional assessment of the mutant TDGF1 protein using a zebrafish rescue assay.
Main Results:
- A mutation was identified in the conserved CFC domain of TDGF1 in a patient with midline forebrain anomalies.
- The identified mutant TDGF1 protein demonstrated inactivity in the zebrafish rescue assay.
Conclusions:
- TDGF1 plays a significant role in human midline and forebrain development.
- Mutations in TDGF1 can lead to congenital anomalies.
- The findings highlight the importance of NODAL signaling pathway components in human embryogenesis.