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Two mutations in Marfan syndrome resulting in truncated fibrillin polypeptides
K Kainulainen1, L Y Sakai, A Child
1Laboratory of Molecular Genetics, National Public Health Institute, Helsinki, Finland.
Abstract:
Biochemical and molecular genetic studies have recently suggested that mutations in the gene coding for fibrillin on chromosome 15 result in Marfan syndrome. To our knowledge, only one mutation in the fibrillin gene has been published. Here we report the results of screening 20 unrelated MFS patients for mutations in fibrillin cDNA by the single-strand conformation polymorphism technique. We found two mutations, both of which appear in the heterozygote form and code for a shortened fibrillin polypeptide. The first mutation is a large in-frame deletion of 366 bases of the fibrillin mRNA, shown to result in a truncated but secreted polypeptide found in the fibroblast culture of the patient. The second mutation is a G-to-A transition resulting in the substitution of a stop codon for a tryptophan codon and thus predicting the premature termination of the polypeptide chain. We screened 60 other, unrelated MFS patients for these mutations as well as for the previously reported mutation (arginine-239 to proline) and found none of the three mutations in any of these patients. These data suggest that most MFS families carry their own distinct mutation.
Insights
Researchers identified two novel mutations in the fibrillin gene causing Marfan syndrome (MFS). Most MFS families appear to have unique genetic mutations, suggesting limited recurrence of specific fibrillin gene defects.
Area of Science:
- Genetics
- Molecular Biology
- Biochemistry
Background:
- Marfan syndrome (MFS) is a genetic disorder affecting connective tissue.
- Recent studies link MFS to mutations in the fibrillin gene on chromosome 15.
- Only one fibrillin gene mutation had been previously documented.
Purpose of the Study:
- To screen unrelated Marfan syndrome patients for mutations in the fibrillin gene.
- To identify novel genetic defects responsible for Marfan syndrome.
- To investigate the diversity of fibrillin gene mutations in MFS patients.
Main Methods:
- Screening of fibrillin cDNA in 20 unrelated MFS patients using single-strand conformation polymorphism (SSCP).
- Analysis of identified mutations for their effect on fibrillin polypeptide structure.
- Further screening of 60 additional MFS patients for identified and previously reported mutations.
Main Results:
- Two novel heterozygous mutations in the fibrillin gene were identified in MFS patients.
- Mutation 1: A 366-base in-frame deletion in fibrillin mRNA, leading to a truncated, secreted polypeptide.
- Mutation 2: A G-to-A transition creating a premature stop codon, resulting in polypeptide chain termination.
- Screening of additional patients did not reveal these mutations or the previously reported mutation, suggesting high mutation-specific diversity.
Conclusions:
- The study identified two new mutations in the fibrillin gene associated with Marfan syndrome.
- The findings indicate that most Marfan syndrome families harbor distinct, private mutations in the fibrillin gene.
- This suggests a broad spectrum of genetic heterogeneity underlying Marfan syndrome.