Abstract.
We have studied a patient with Marfan syndrome whose mutation was not detected by heteroduplex analysis. Primary cultured patient fibroblasts were metabolically labelled and found to secrete fibrillin-1 defectively when compared with an age-matched control. Sequencing of patient cDNA, isolated by reverse transcription-polymerase chain reaction of patient fibroblast RNA, detected a 33-bp insertion. The reading frame of the mutant allele was maintained and predicted the insertion of 11 amino acids at the beginning of calcium-binding epidermal growth factor-like domain 29. Direct sequencing of genomic DNA detected a heterozygous G+1→A transversion in intron 46 of FBN1. The 11 amino acid insertion was the consequence of the usage of a cryptic splice site 33-bp downstream of the mutation. This is the first reported case of a splicing defect in FBN1 leading to the production of a full-length fibrillin-1 transcript containing a large amino acid insertion.
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Hutchinson, S., Wordsworth, P.B. & Handford, P.A. Marfan syndrome caused by a mutation in FBN1 that gives rise to cryptic splicing and a 33 nucleotide insertion in the coding sequence. Hum Genet 109, 416–420 (2001). https://doi.org/10.1007/s004390100573
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DOI: https://doi.org/10.1007/s004390100573