Identification of 29 novel and nine recurrent fibrillin-1 (FBN1) mutations and genotype-phenotype correlations in 76 patients with Marfan syndrome.

Abstract

Marfan syndrome (MFS) is an autosomal-dominant disorder of the fibrous connective tissue that is typically caused by mutations in the gene coding for fibrillin-1 (FBN1), a major component of extracellular microfibrils. The clinical spectrum of MFS is highly variable and includes involvement of the cardiovascular, skeletal, ocular, and other organ systems; however, the genotype-phenotype correlations have not been well developed. Various screening methods have led to the identification of about 600 different mutations (FBN1-UMD database; www.umd.be). In this study we performed SSCP and/or direct sequencing to analyze all 65 exons of the FBN1 gene in 116 patients presenting with classic MFS or related phenotypes. Twenty-nine novel and nine recurrent mutations were identified in 38 of the analyzed patients. The mutations comprised 18 missense (47%), eight nonsense (21%), and five splice site (13%) mutations. Seven further mutations (18%) resulted from deletion, insertion, or duplication events, six of which led to a frameshift and subsequent premature termination. Additionally, we describe new polymorphisms and sequence variants. On the basis of the data presented here and in a previous study, we were able to establish highly significant correlations between the FBN1 mutation type and the MFS phenotype in a group of 76 mutation-positive patients for whom comprehensive clinical data were available. Most strikingly, there was a significantly lower incidence of ectopia lentis in patients who carried a mutation that led to a premature termination codon (PTC) or a missense mutation without cysteine involvement in FBN1, as compared to patients whose mutations involved a cysteine substitution or splice site alteration.

• Authors: Kathrin Rommel, Matthias Karck, Axel Haverich, Yskert von Kodolitsch, Meike Rybczynski, Götz Müller, Krishna K Singh, Jörg Schmidtke, Mine Arslan-Kirchner
• Journal: Human mutation (Hum Mutat) Vol. 26 Issue 6 Pg. 529-39 (Dec 2005) ISSN: 1098-1004 [Electronic] United States
• PMID: 16220557 (Publication Type: Journal Article)
• Copyright: Copyright 2005 Wiley-Liss, Inc.

Chemical References

• FBN1 protein, human
• Fibrillin-1
• Fibrillins
• Microfilament Proteins
• Cysteine

Topics

• Amino Acid Sequence
• Cysteine (genetics)
• DNA Mutational Analysis
• Fibrillin-1
• Fibrillins
• Genetic Testing
• Genotype
• Humans
• Marfan Syndrome (diagnosis, genetics)
• Meta-Analysis as Topic
• Microfilament Proteins (chemistry, genetics)
• Mutation
• Phenotype
• Polymorphism, Genetic