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Clinical and genetic associations in Marfan syndrome and related disorders
1Brookdale Center for Molecular Biology, Mount Sinai School of Medicine, New York, NY 10029.
Abstract:
Although Marfan syndrome has been a recognized clinical entity for nearly a century, only in the early 1950s were its manifestations and genetic features firmly and fully established. Similarly, although the identification of the basic defect in Marfan syndrome had been vigorously pursued for several decades, it was only in 1991 that two independent reports implicated fibrillin as the defective gene product. Surprisingly and serendipitously, these studies also revealed genetic heterogeneity of the fibrillin proteins and established linkage between one of these loci and a Marfan-related disorder, congenital contractural arachnodactyly. Like Marfan syndrome, this condition is accompanied by skeletal abnormalities; however, flexion joint contractures replace the loose-jointedness of Marfan syndrome and, more importantly, neither the eye nor the aorta are affected. More recently, a similar association with the fibrillin gene has also been established in the dominantly inherited form of ectopia lentis. These associations of structurally related gene products with Marfan and related syndromes may conceivably imply that other connective tissue disorders are caused by mutations in these or other yet undiscovered fibrillin genes.
Insights
Fibrillin gene defects cause Marfan syndrome and related disorders like congenital contractural arachnodactyly and ectopia lentis, highlighting genetic heterogeneity in connective tissue diseases.
Area of Science:
- Genetics
- Molecular Biology
- Connective Tissue Diseases
Background:
- Marfan syndrome, a recognized clinical entity for nearly a century, had its genetic features established in the 1950s.
- Identification of the basic defect in Marfan syndrome was pursued for decades before implicating fibrillin in 1991.
Purpose of the Study:
- To summarize the genetic basis of Marfan syndrome and related disorders.
- To explore the role of fibrillin gene mutations in connective tissue diseases.
Main Methods:
- Review of historical and recent genetic studies on Marfan syndrome and related conditions.
- Genetic linkage analysis and gene product identification.
Main Results:
- Fibrillin was identified as the defective gene product in Marfan syndrome in 1991.
- Genetic heterogeneity of fibrillin proteins was revealed, with linkage to congenital contractural arachnodactyly.
- Fibrillin gene association also established for dominantly inherited ectopia lentis.
Conclusions:
- Mutations in fibrillin genes are associated with Marfan syndrome, congenital contractural arachnodactyly, and ectopia lentis.
- These findings suggest potential roles for fibrillin gene mutations in other connective tissue disorders.
- Further research into undiscovered fibrillin genes may uncover additional causes of connective tissue diseases.