Clustering of mutations associated with mild Marfan-like phenotypes in the 3? region ofFBN1 suggests a potential genotype-phenotype correlation

Palz, Monika; Tiecke, Frank; Booms, Patrick; Göldner, B.; Rosenberg, Thomas; Fuchs, Josefine; Skovby, Flemming; Schumacher, Hanna; Kaufmann, U; Kodolitsch, Y. von; Nienaber, C.A.; Leitner, Christoph; Katzke, Stefanie; Vetter, Barbara; Hagemeier, Christian; Robinson, Peter N.

doi:10.1002/(sici)1096-8628(20000320)91:3<212::aid-ajmg12>3.0.co;2-3

Cited by 63 publications

(45 citation statements)

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“…A clustering of mutations associated with the most severe form of MFS-neonatal Marfan syndrome-has been noted in a region encompassing exons 24 to 32 . A cluster of mutations associated with the mild phenotype, typified by a lack of significant aortic pathology, is located in exons 59 to 65 (Palz et al 2000). However, genotype-phenotype correlations have been slow to emerge.…”

Section: Introductionsupporting

confidence: 55%

The FBN1 (R2726W) mutation is not fully penetrant

Buoni¹,

Zannolli²,

Macucci³

et al. 2004

Annals of Human Genetics

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SummaryThe R2726W mutation in the fibrillin 1 (FBN1, Marfan syndrome) gene segregates with isolated skeletal features of Marfan syndrome and/or high stature. Here we report a family in which two out of four individuals, an 18-year-old son and his mother, a 41-year-old woman, had the R2726W mutation of FBN1. Both family members carrying the mutation were of average height. The son had a Marfan-like phenotype, but his mother did not. The FBN1 R2776W mutation, which is associated with skeletal features of Marfan syndrome, appears incompletely penetrant. Consequently, genetic counselling in the presence of this mutation is difficult.

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Section: Introductionsupporting

confidence: 55%

The FBN1 (R2726W) mutation is not fully penetrant

Buoni¹,

Zannolli²,

Macucci³

et al. 2004

Annals of Human Genetics

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“…10 By directing the orientation of elastin fibers, fibrillin-1 microfibrils play a vital role in load bearing. 10 Fibrillin-1 contains a large number of calcium-binding, epidermal growth factor repeats, in which mutations have been associated with both Marfan syndrome 22,23 and abdominal aortic aneurysms. 24 The mechanism linking the VNTR polymorphism examined in the current study with a functional correlate has not been determined; however, there are many precedents for linkage between intron polymorphisms and effects on gene expression.…”

Section: Circulation February 19 2002mentioning

confidence: 68%

Fibrillin-1 Genotype Is Associated With Aortic Stiffness and Disease Severity in Patients With Coronary Artery Disease

Medley¹,

Cole²,

Gatzka³

et al. 2002

Circulation

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Background-Elevated pulse pressure is associated strongly with adverse cardiovascular outcome; however, the genetic basis of this condition is unknown. This study examined whether genotypic variation in the extracellular matrix protein fibrillin-1, the Marfan gene, was associated with aortic stiffening and therefore could contribute to cardiovascular risk associated with pulse pressure elevation in coronary disease. Methods and Results-Patients (nϭ145; 113 men), 62Ϯ9 years of age (meanϮSD), with angiographically confirmed coronary disease, were studied. Carotid applanation tonometry was used to assess central blood pressures, and in conjunction with Doppler velocimetry, to assess aortic input and characteristic impedance. Fibrillin-1 genotype was characterized by a variable nucleotide tandem repeat and 2 single-nucleotide polymorphisms. The variable nucleotide tandem repeat was a good predictor of underlying haplotypes with 3 genotypes (2-2, 2-4, and 2-3) accounting for 86% of the population. The 2-3 genotype had higher input impedance (Pϭ0.002), characteristic impedance (Pϭ0.005), and carotid pulse pressure (Pϭ0.002) compared with the 2-2 and 2-4 genotypes. Disease severity assessed by previous angioplasties and the number of patients with a stenosis Ͼ90% was also greater in the 2-3 genotype. Furthermore, in a multivariate analysis, fibrillin-1 genotype and central pulse pressure were independent of conventional risk factors in determining coronary disease severity. There was no difference in age, sex ratio, body mass index, smoking status, cholesterol level, or medication among the 3 genotypes. Conclusions-Although

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“…This mutation is in the C-terminal part of the protein and was found in a patient with MFS, with skeletal, ocular and pulmonary, but no cardiac involvement. 12 In conclusion, if the Arg485Cys substitution had been found heterozygously in a patient with MFS or isolated ectopia lentis, we would have had no doubt about the pathogenic effect of the mutation.…”

Section: Resultsmentioning

confidence: 99%