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Published on: November 22, 2013
In Silico Analyses Reveal the Relationship Between SIX1/EYA1 Mutations and Conotruncal Heart Defects
Bojian Li1, Lijuan Xu1, Nanchao Hong1
1Department of Pediatric Cardiology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
Conotruncal heart defects (CTDs) represent a group of severe and complicated congenital cardiovascular malformations and require opportune clinical interventions once diagnosed. Occurrence of CTD is related to the functional abnormality of the second heart field (SHF), and variants of genes which regulate the development of the second heart field have been recognized as the main genetic factors leading to CTDs. Previous studies indicated that transcriptional complex SIX1/EYA1 may contribute to SHF development, and SIX1/EYA1 knockout mice exhibited a series of conotruncal malformations. Here, we recruited and sequenced 600 Chinese conotruncal heart defect patients and 300 controls. We screened out one novel SIX1 mutation (SIX1-K134R) and four EYA1 rare mutations (EYA1-A227T, EYA1-R296H, EYA1-Q397R, EYA1-G426S), all variants were present only in the case cohort, and the mutated sites were highly conserved. We then analyzed mutations by software including Sift, PolyPhen-2, PROVEAN, Mutation Taster, HOPE, and SWISS-PdbViewer. The results showed that the mutations had varying degrees of pathogenic risk, protein properties, spatial conformations, and domain functions which might be altered or influenced. Through biological and in silico analyses, our study suggests an association between SIX1/EYA1 mutations and cardiovascular malformations, SIX1/EYA1 mutations might be partially responsible for CTDs.
Insights
Genetic variants in SIX1/EYA1 may contribute to conotruncal heart defects (CTDs), a severe congenital cardiovascular malformation. This study identified novel SIX1 and EYA1 mutations in Chinese patients with CTDs, suggesting a potential genetic link.
Area of Science:
- Genetics
- Developmental Biology
- Cardiology
Background:
- Conotruncal heart defects (CTDs) are severe congenital cardiovascular malformations linked to the second heart field (SHF).
- Gene variants regulating SHF development are key genetic factors in CTDs.
- The SIX1/EYA1 transcriptional complex is implicated in SHF development, with SIX1/EYA1 knockout mice showing CTDs.
Purpose of the Study:
- To investigate the association between SIX1/EYA1 gene mutations and CTDs in a Chinese population.
- To identify novel mutations in SIX1 and EYA1 associated with CTDs.
Main Methods:
- Sequencing of 600 Chinese CTD patients and 300 controls.
- Identification and analysis of SIX1 and EYA1 mutations using bioinformatics tools (Sift, PolyPhen-2, PROVEAN, Mutation Taster, HOPE, SWISS-PdbViewer).
Main Results:
- One novel SIX1 mutation (SIX1-K134R) and four rare EYA1 mutations (EYA1-A227T, EYA1-R296H, EYA1-Q397R, EYA1-G426S) were identified exclusively in the CTD cohort.
- These mutations were located in highly conserved sites.
- In silico analyses indicated varying degrees of pathogenic risk and potential alterations in protein properties, spatial conformations, and domain functions.
Conclusions:
- The study suggests a significant association between SIX1/EYA1 mutations and cardiovascular malformations.
- SIX1/EYA1 mutations may play a partial role in the pathogenesis of CTDs.
