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Published on: August 15, 2019
A missense T (Brachyury) mutation contributes to vertebral malformations
Nader Ghebranious1, Robert D Blank, Cathleen L Raggio
1Molecular Diagnostic Research Laboratory, Marshfield Clinic, Marshfield, Wisconsin 54449, USA.
Summary
Mutations in the T gene (Brachyury) are linked to human congenital vertebral malformations (CVM). This study identifies a specific T gene variant associated with CVM, offering new insights into skeletal development disorders.
Area of Science:
- Genetics
- Developmental Biology
- Skeletal Biology
Background:
- Congenital vertebral malformations (CVM) are complex skeletal disorders with unidentified genetic causes.
- Body patterning genes, crucial for axial skeletal development, are candidates for CVM susceptibility.
Purpose of the Study:
- To investigate the role of the T (Brachyury) and TBX6 genes in the pathogenesis of sporadic human CVMs.
- To identify genetic variants in T and TBX6 associated with CVM occurrence.
Main Methods:
- Sequencing of the T and TBX6 genes (coding regions, splice junctions, and promoter regions) in 50 patients with CVM.
- Variant analysis in patient-parent trios and a large reference population.
- Functional assessment of identified variants.
Main Results:
- A missense variant (c.1013C>T, Ala338Val) in the T gene was identified in three unrelated CVM patients and their unaffected parents.
- This T gene variant showed a significant association with CVM (p < 0.001) and is evolutionarily conserved.
- No pathogenic TBX6 variants were found in the CVM patients.
Conclusions:
- The T gene missense variant (c.1013C>T) is pathogenic and represents the first identified association with sporadic human CVMs.
- TBX6 mutations do not appear to be a significant cause of CVM.
- Epistatic interactions between T variants and other genetic/environmental factors may influence CVM phenotypes.
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