Novel mutations of AXIN2 identified in a Chinese Congenital Heart Disease Cohort
| Autor: | Hongyan Wang, Xue-Yan Yang, Pei-Cheng Ding, Peiqiang Li, Bin Qiao, Mengjiao Zhu, Fengshan Chen, Yun-Qian Gao, Han-Fei Tang, Rui Peng, Yufang Zheng, Xiaoyun Ma, Lei Lu |
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| Rok vydání: | 2019 |
| Předmět: |
Heart Defects
Congenital Male 0301 basic medicine China Heart disease Mutation Missense 030105 genetics & heredity Biology Bioinformatics medicine.disease_cause Cohort Studies Mice 03 medical and health sciences Asian People Axin Protein Genetics AXIN2 medicine Animals Humans Missense mutation Child Wnt Signaling Pathway Zebrafish Genetics (clinical) Gene knockdown Mutation Wnt signaling pathway High-Throughput Nucleotide Sequencing Infant biology.organism_classification medicine.disease Phenotype 030104 developmental biology Amino Acid Substitution Child Preschool Gene Knockdown Techniques Female |
| Zdroj: | Journal of Human Genetics. 64:427-435 |
| ISSN: | 1435-232X 1434-5161 |
| Popis: | Congenital heart defects (CHDs), the most common congenital human birth anomalies, involves complex genetic factors. Wnt/β-catenin pathway is critical for cardiogenesis and proved to be associated with numerous congenital heart abnormities. AXIN2 has a unique role in Wnt/β-catenin pathway, as it is not only an important inhibitor but also a direct target of Wnt/β-catenin pathway. However, whether AXIN2 is associated with human CHDs has not been reported. In our present study, we found a differential expression of Axin2 mRNA during the development of mouse heart, indicating its importance in mouse cardiac development. Then using targeted next-generation sequencing, we found two novel case-specific rare mutations [c.28 C > T (p.L10F), c.395 A > G (p.K132R)] in the sequencing region of AXIN2. In vitro functional analysis suggested that L10F might be a loss-of-function mutation and K132R is a gain-of-function mutation. Both mutations disrupted Wnt/β-catenin pathway and failed to rescue CHD phenotype caused by Axin2 knockdown in zebrafish model. Collectively, our study indicates that rare mutations in AXIN2 might contribute to the risk of human CHDs and a balanced canonical Wnt pathway is critical for cardiac development process. To our knowledge, it is the first study of AXIN2 mutations associated with human CHDs, providing new insights into CHD etiology. |
| Databáze: | OpenAIRE |
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