ArticleAmerican journal of human genetics1999
Cysteine substitutions in epidermal growth factor-like domains of fibrillin-1: distinct effects on biochemical and clinical phenotypes.
Article in American journal of human genetics, 1999. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 88 papers.
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88 citing papers in PubMed, 228 citations in OpenAlex.
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- Pain Hypersensitivity in a Mouse Model of Marfan Syndrome.Antioxidants (Basel, Switzerland) · 2026Article
- Characterisation of Type-1 Fibrillinopathies in a Sri Lankan Cohort: Genotype-Phenotype Correlations and Novel FBN1 Variants.Molecular syndromology · 2025Article
- Intrinsic cardiomyopathy in pediatric Marfan syndrome: predictive factors and risk assessments.Pediatric research · 2025Article
- Novel De Novo DLL4 Missense and Highly Accurate Protein Structure Prediction in Adams-Oliver Type 6 Syndrome.Clinical case reports · 2025Article
- Developing a more accurate population frequency of Marfan syndrome from predicted pathogenic FBN1 variants in the gnomAD cohorts.Scientific reports · 2025Article
- Sticky organisms create underwater biological adhesives driven by interactions between EGF- and GlcNAc- containing polysaccharides.Nature communications · 2025Article
- A novel missense variant ofFrontiers in pediatrics · 2025Article
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- Identification of Genetic Variants Associated with Hereditary Thoracic Aortic Diseases (HTADs) Using Next Generation Sequencing (NGS) Technology and Genotype-Phenotype Correlations.International journal of molecular sciences · 2024Article
- Mid- to long-term radiological and respiratory outcomes following surgery for older early-onset scoliosis patients with Marfan syndrome.Scientific reports · 2024Article
- A Novel Heterozygous Intronic FBN1 Variant Contributes to Aberrant RNA Splicing in Marfan Syndrome.Molecular genetics & genomic medicine · 2024Article
- Functional characterization of 2,832 JAG1 variants supports reclassification for Alagille syndrome and improves guidance for clinical variant interpretation.American journal of human genetics · 2024Article
- Contributions of Germline and Somatic Mosaic Genetics to Thoracic Aortic Aneurysms in Nonsyndromic Individuals.Journal of the American Heart Association · 2024Article
- Causative role of a novel intronic indel variant in FBN1 and maternal germinal mosaicism in Marfan syndrome.Orphanet journal of rare diseases · 2024Article
- Genetic models of fibrillinopathies.Genetics · 2024Review
- Clinical and Genetic Landscape of Ectopia Lentis Based on a Cohort of Patients From 156 Families.Investigative ophthalmology & visual science · 2024Article
- Disruption of FBN1 by an Alu element insertion: A novel genetic cause of Marfan syndrome.European journal of medical genetics · 2023Article
- CysDB: a human cysteine database based on experimental quantitative chemoproteomics.Cell chemical biology · 2023Article
28 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Fibrillin-1 (FBN1) contains 47 epidermal growth factor (EGF)-like domains characterized by six conserved cysteine residues. Cysteine substitutions that disrupt one of the three disulfide bonds are frequent causes of Marfan syndrome (MFS). We identified 19 new substitutions involving cysteine residues in each of the six positions of EGF-like domains. Allele-specific mRNA assays revealed equal abundance of mutant and normal FBN1 transcripts in all 10 individuals studied. Quantitative pulse-chase analysis of fibrillin protein was performed on 25 mutant fibroblast strains with substitutions of 22 different cysteine residues in 18 different EGF-like domains spanning the entire gene. Normal synthesis and stability of mutant fibrillin molecules was seen in 20/25 individuals, 11 of whom showed delayed intracellular processing and/or secretion. In the remaining five cases, the mutant protein was apparently unstable. In four of these five cases, the second or third disulfide bond of EGF-like domains immediately preceding an 8-cysteine or hybrid domain was affected. All but two mutations caused severe reduction of matrix deposition, which was attributed to a dominant-negative effect of mutant molecules. For genotype/phenotype comparisons, clinical data on 25 probands and 19 mutation-positive family members were analyzed. Ocular manifestations were among the most consistent features (ectopia lentis in 86%, myopia in 80%). Nine mutations encoded by exons 26-32 resulted in early-onset classic MFS and, in one case, neonatal-lethal MFS. Mutations outside this region were associated with variable clinical phenotypes, including individuals with fibrillinopathies not meeting diagnostic criteria for MFS.
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