title: 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.affiliation: Institute of Human Genetics, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Rommel
authors.forename: Matthias
authors.initials: M
authors.lastname: Karck
authors.forename: Axel
authors.initials: A
authors.lastname: Haverich
authors.forename: Yskert
authors.initials: Y
authors.lastname: von Kodolitsch
authors.forename: Meike
authors.initials: M
authors.lastname: Rybczynski
authors.forename: Götz
authors.initials: G
authors.lastname: Müller
authors.forename: Krishna K
authors.initials: KK
authors.lastname: Singh
authors.forename: Jörg
authors.initials: J
authors.lastname: Schmidtke
authors.forename: Mine
authors.initials: M
authors.lastname: Arslan-Kirchner
mesh_terms: D000595:Amino Acid Sequence; D003545:Cysteine / Q000235:genetics; D004252:DNA Mutational Analysis; D000071838:Fibrillin-1; D000071837:Fibrillins; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008382:Marfan Syndrome / Q000175:diagnosis* / Q000235:genetics*; D015201:Meta-Analysis as Topic; D008840:Microfilament Proteins / Q000737:chemistry / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D011110:Polymorphism, Genetic; D054392:Adipokines
chemical_list: D003545:Cysteine; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines