Characterization of FBN1 c.5917+6T>C in transfected HEK293 cells demonstrated that it caused skipping of exon 47, leading to the loss of the 33th calcium binding epidermal growth factor-like domain associated with Marfan syndrome.
We recommend that echocardiogram, ocular examination and FBN1 molecular testing be considered for any patients with possible MFS even in the absence of skeletal features, including Hispanic patients.
In conclusion, we were able to detect FBN1 mutations in 88% of patients with MFS and in 36% of patients with other fibrillinopathies type I, confirming that FBN1 mutations are good predictors of classic MFS.
On the basis of the data presented here and in a previous study, we were able to establish highly significant correlations between the FBN1 mutation type and the MFS phenotype in a group of 76 mutation-positive patients for whom comprehensive clinical data were available.
These results expand and further strengthen the concept that proteolytic degradation of mutated fibrillin-1 might be an important potential mechanism in the pathogenesis of Marfan syndrome and other disorders caused by mutations in fibrillin-1.
To explore this possibility, firstly we analyzed FBN1 allelic variants in 12 Japanese patients with MFS, and secondly we analyzed fibrillin-3 gene ( FBN3) in patients without FBN1 mutations using conformation sensitive gel electrophoresis (CSGE) and direct sequencing analysis.
The mutation detection rate in this study was 42% overall, but was only 12% in individuals not fulfilling the diagnostic criteria for MFS, suggesting that clinical overdiagnosis is one reason for the low detection rate observed for FBN1 mutation analysis.
Setting up CSGE analysis for the FBN1 gene and testing the method first by screening coded samples from 17 MFS patients with previously detected FBN1 mutations.
A third family cosegregates mild mitral valve prolapse syndrome with a mutation in FBN1 that can be functionally distinguished from those associated with the classic MFS phenotype.
In this study we screened all 65 exons of the fibrillin-1 gene in 20 Marfan syndrome families where at least two affected individuals were characterised and available for analysis, another 30 families with only one affected member available for analysis, and in 10 sporadic cases.
Fibrillin-1 mutations have also been found in several other related connective tissue disorders, such as severe neonatal Marfan syndrome, dominant ectopia lentis, familial ascending aortic aneurysm, isolated skeletal features of Marfan syndrome, and Shprintzen-Goldberg syndrome.