Multi-exon deletions of the <it>FBN1</it> gene in Marfan syndrome
<p>Abstract</p> <p>Background</p> <p>Mutations in the fibrillin -1 gene <it>(FBN1)</it> cause Marfan syndrome (MFS), an autosomal dominant multi-system connective tissue disorder. The 200 different mutations reported in the 235 kb, 65 exon-containing gene in...
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| Main Authors: | , , , , |
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| Format: | Book |
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BMC,
2001-10-01T00:00:00Z.
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| Online Access: | Connect to this object online. |
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| Summary: | <p>Abstract</p> <p>Background</p> <p>Mutations in the fibrillin -1 gene <it>(FBN1)</it> cause Marfan syndrome (MFS), an autosomal dominant multi-system connective tissue disorder. The 200 different mutations reported in the 235 kb, 65 exon-containing gene include only one family with a genomic multi-exon deletion.</p> <p>Methods</p> <p>We used long-range RT-PCR for mutation detection and long-range genomic PCR and DNA sequencing for identification of deletion breakpoints, allele-specific transcript analyses to determine stability of the mutant RNA, and pulse-chase studies to quantitate fibrillin synthesis and extracellular matrix deposition in cultured fibroblasts. Southern blots of genomic DNA were probed with three overlapping fragments covering the <it>FBN1</it> coding exons</p> <p>Results</p> <p>Two novel multi-exon <it>FBN1</it> deletions were discovered. Identical nucleotide pentamers were found at or near the intronic breakpoints. In a Case with classic MFS, an in-frame deletion of exons 42 and 43 removed the C-terminal 24 amino acids of the 5<sup>th</sup> LTBP (8-cysteine) domain and the adjacent 25<sup>th</sup> calcium-binding EGF-like (6-cysteine) domain. The mutant mRNA was stable, but fibrillin synthesis and matrix deposition were significantly reduced. A Case with severe childhood-onset MFS has a <it>de novo</it> deletion of exons 44-46 that removed three EGF-like domains. Fibrillin protein synthesis was normal, but matrix deposition was strikingly reduced. No genomic rearrangements were detected by Southern analysis of 18 unrelated MFS samples negative for <it>FBN1</it> mutation screening.</p> <p>Conclusions</p> <p>Two novel deletion cases expand knowledge of mutational mechanisms and genotype/phenotype correlations of fibrillinopathies. Deletions or mutations affecting an LTBP domain may result in unstable mutant protein cleavage products that interfere with microfibril assembly.</p> |
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| Item Description: | 10.1186/1471-2350-2-11 1471-2350 |