Marfan syndrome caused by a mutation in FBN1 that gives rise to cryptic splicing and a 33 nucleotide insertion in the coding sequence

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 re...

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Bibliographic Details
Published in:	Human genetics 2001-10, Vol.109 (4), p.416-420
Main Authors:	HUTCHINSON, Sarah, WORDSWORTH, B. Paul, HANDFORD, Penny A
Format:	Article
Language:	eng
Subjects:	Adult Alternative Splicing - genetics Amino Acid Sequence Base Sequence Biological and medical sciences Cysteine - genetics Cysteine - metabolism DNA Mutational Analysis Exons - genetics Fibrillin-1 Fibrillins Fibroblasts Fundamental and applied biological sciences. Psychology Heteroduplex Analysis Humans Male Marfan Syndrome - genetics Microfilament Proteins - biosynthesis Microfilament Proteins - chemistry Microfilament Proteins - genetics Microfilament Proteins - secretion Molecular and cellular biology Molecular Sequence Data Mutagenesis, Insertional - genetics Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - genetics RNA, Messenger - metabolism
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Summary:	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.
ISSN:	0340-6717 1432-1203