ClinVar

Liu et al. (1997) carried out a systematic mutation search of PCR-amplified transcripts of the FBN1 gene from patients with Marfan syndrome (154700). By long RT-PCR and restriction enzyme digestions, they identified skipping of FBN1 exons in 10% of Marfan cases. All but 1 of these were due to sequence alterations at splice sites. In skin fibroblasts derived from a patient with classic Marfan syndrome, an abnormally migrating restriction fragment was identified and found to represent deletion of 66 bp due to in-frame skipping of the entire exon 51. This exon encodes the 3-prime portion of 1 of the 7 8-cysteine domains in FBN1 that is similar to a motif found in transforming growth factor-beta-1 binding protein (150390). Sequencing of exon 51 and surrounding splice sites, amplified from genomic DNA with intron primers, identified only 1 sequence variation unique to this sample: a C-to-T transition (6354C-T) at position +41 of exon 51. This mutation changes codon 2118 from AUC to AUU, both of which encode isoleucine. Liu et al. (1997) stated that this nucleotide change is unlikely to affect known binding sites of the splicing machinery. Further studies indicated that the skipping of exon 51 in these cells was due solely to the silent mutation, 6354C-T. Skipping of exon 51 associated with a 6339T-G mutation that changes a tyrosine (TAT) to a termination (TAG) codon (134797.0008) was previously reported as the cause of exon 51 skipping (Dietz et al., 1993; Dietz and Kendzior, 1994). Liu et al. (1997) commented that skipping caused by a silent mutation suggests the existence of an alternative mechanism of exon skipping yet to be discovered.