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ENU induced mutations causing congenital cardiovascular anomalies
Qing Yu1, Yuan Shen, Bishwanath Chatterjee
1Laboratory of Developmental Biology, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892-8019, USA.
Development (Cambridge, England)
|November 19, 2004
Summary
High-frequency ultrasound screening of N-ethyl-N-nitrosourea (ENU) mutagenized mouse fetuses identified numerous congenital cardiovascular defects. This study demonstrates the effectiveness of ENU mutagenesis and ultrasound phenotyping for discovering new genetic causes of heart disease.
Area of Science:
- Genetics
- Developmental Biology
- Cardiovascular Research
Background:
- Congenital cardiovascular anomalies are a significant cause of infant mortality.
- Understanding the genetic basis of these defects is crucial for developing effective treatments.
- Existing genetic models may not capture the full spectrum of human congenital heart disease.
Purpose of the Study:
- To establish an efficient method for identifying novel genetic mutations causing congenital heart defects (CHDs) in mice.
- To utilize high-throughput ultrasound phenotyping to screen mutagenized mouse populations.
- To map and identify the genetic underpinnings of newly discovered CHDs.
Main Methods:
- Non-invasive high-frequency ultrasound was used to screen 7546 mouse fetuses from 262 N-ethyl-N-nitrosourea (ENU) mutagenized families.
- Congenital cardiovascular anomalies were identified and documented.
- Mutations in affected families were mapped using polymorphic microsatellite DNA markers.
- Specific genes (Sema3CL605P, Gja1W45X) were identified in two families.
Main Results:
- 124 families with cardiovascular defects were identified, exhibiting a wide range of clinically relevant CHDs.
- Mutations were mapped to specific chromosomal regions, including mouse chromosomes 4 and 2.
- Phenotypes observed included ventricular septal defects, transposition of the great arteries, persistent truncus arteriosus, and coronary aneurysms.
- Identified mutations included Sema3CL605P and Gja1W45X, associated with specific cardiac malformations.
- Some mutations exhibited phenotypes in both heterozygous and homozygous animals.
Conclusions:
- ENU mutagenesis combined with high-throughput ultrasound is highly effective for discovering mutations causing diverse congenital heart defects.
- This approach successfully identified novel genetic mutations and mapped them to specific chromosomal locations.
- The identified ENU-induced mutations provide valuable models for studying the genetic basis of human congenital heart disease and may reveal new insights into disease mechanisms.