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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.

Original publication

DOI

10.1007/s004390100573

Type

Journal article

Journal

Hum Genet

Publication Date

10/2001

Volume

109

Pages

416 - 420

Keywords

Adult, Alternative Splicing, Amino Acid Sequence, Base Sequence, Cysteine, DNA Mutational Analysis, Exons, Fibrillin-1, Fibrillins, Fibroblasts, Heteroduplex Analysis, Humans, Male, Marfan Syndrome, Microfilament Proteins, Molecular Sequence Data, Mutagenesis, Insertional, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction