A novel de novo mutation in exon 14 of the fibrillin-1 gene associated with delayed secretion of fibrillin in a patient with a mild Marfan phenotype

Abstract

The Marfan syndrome, an autosomal dominant heritable disorder of connective tissue, is caused by mutations in the gene for fibrillin-1, FBN1. A novel FBN1 mutation was identified using temperature-gradient gel electrophoresis of a reverse-transcribed polymerase chain reaction product spanning exons 14 to 16. The mutation, G1760A, is predicted to result in the amino acid substitution C587Y and thus to disrupt one of the disulfide bonds of the calcium-binding epidermal growth factor-like module encoded by exon 14. C587Y was found to be a de novo mutation in a relatively mildly affected 15-year-old girl whose clinical phenotype was characterized mainly by ectopia lentis and thoracic scoliosis. Metabolic labeling of cultured dermal fibroblasts from the affected patient demonstrated delayed secretion of fibrillin with normal synthesis and no decrease in incorporation into the extracellular matrix compartment. Fibrillin immunostaining of confluent dermal fibroblast cultures revealed no visible difference between the patient's cells and control cells. Characterization of many different FBN1 mutations from different regions of the gene may provide a better understanding of clinical and biochemical genotype-phenotype relationships.

TGGE screening of the entireFBN1coding sequence in 126 individuals with marfan syndrome and related fibrillinopathies

“…Clinical data concerning affected individuals is summarized in Table 2, and unusual features are described above in separate clinical summaries. Some results of this study concerning genotypephenotype relations in specific regions of FBN1 have already been presented [Booms et al, 1999;Booms et al, 1997;Palz et al, 2000;Tiecke et al, 2001]. In this report, we describe PCR and TGGE conditions for FBN1 exons 1-23 and 41-58, and present 33 mutations in these exons.…”

“…However, the mutation C2221G was found as a recurrent mutation in an unrelated woman who had developed an acute rupture of the ascending aorta during the 30th week of gestation (B37). One individual with a de novo mutation in exon 14 (B3:C587Y) that we had initially identified by TGGE screening of cDNA fragment [Booms et al, 1997], had relatively mild involvement at the age of 16 years, and was considered to have emerging MFS in light of the age-dependent nature of the MFS phenotype.…”

“…Including previously published mutations [Booms et al, 1999;Booms et al, 1997;Palz et al, 2000;Tiecke et al, 2001], we identified a total of 53 mainly novel FBN1 mutations, 33 of which are described here for the first time.…”

A Novel Fibrillin 1 Gene Mutation Leading to Marfan Syndrome with Minimal Cardiac Features

“…The localization of the mutant CaB-EGF domain along the FBN1 polypeptide also appears to influence the severity of the phenotype observed. Cysteine substitutions in the vicinity of C538P on exon 13 (this study) such as C570R on exon 14 (previously 13) [Schrijver et al, 1999], or C587Y on exon 15 (previously 14) [Booms et al, 1997] both result in ectopia lentis with some skeletal and integument features, but no cardiac symptoms. Likewise, more distant substitutions such as C776G [Katzke et al, 2002], or C1782R [Adés et al, 2004] have been also shown to have little cardiac effect.…”

Human Genome and Diseases:¶The molecular pathogenesis of the Marfan syndrome

“…Pulse chase experiments in this system allow measurement of the synthesis, secretion, and ECM aggregation of fibrillin [21]. Patients with MFS display a variety of abnormalities in this system [22][23][24][25].…”