title: Novel mutation in FBN1 causes ectopia lentis and varicose great saphenous vein in one Chinese autosomal dominant family.
abstract: OBJECTIVE
  To identify genetic defects in a Chinese family with ectopia lentis (EL) and varicose great saphenous vein (GSV) and to analyze the correlations between phenotype and genotype.
  
  
  METHODS
  Twenty-two (12 affected subjects and ten unaffected subjects) among 53 members of a Chinese family underwent complete physical, ophthalmic, and cardiovascular examinations. Genomic DNA was extracted from the leukocytes in the subjects' peripheral blood. A minimum interval was achieved with linkage study and haplotype analysis. All 65 exons and the flanking intronic regions of fibrillin-1 (FBN1) were amplified with PCR and screened for mutations with direct Sanger sequencing. Molecular modeling was analyzed in an in silico study.
  
  
  RESULTS
  The linkage study showed a strong cosegregation signal on chromosome 15. The non-parametric linkage analysis yielded a maximum score of 29.1(p<0.00001), and the parametric logarithm of the odds (LOD) score was 3.6. The minimum interval of the shared haplotype was rs1565863-rs877228. The best candidate gene in this region was FBN1. A novel mutation, c.3928G>A, p.1310G>S in exon 31, was identified in FBN1 and cosegregated well in the family. We applied molecular modeling to show the effect of this mutation on the fibrillin-1 structure. The mutation significantly distorts the calcium coordination, decreases the binding of the calcium ion in that motif, and affects the local calcium-binding epidermal growth factor (cbEGF) interface that depends on Ca binding.
  
  
  CONCLUSIONS
  FBN1-associated fibrillinopathies are a group of diseases with dynamic phenotype changes. Novel mutation p.1310G>S was first reported to cause Marfan syndrome (MFS). Our results expand the mutation spectrum in FBN1 and enhance our knowledge of genotype-phenotype correlations underlying FBN1 mutations.
authors.affiliation: Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China ; Department of Ophthalmology, North Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Fu
authors.affiliation: Department of Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Vascular Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Qingsheng
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Shen
authors.affiliation: Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Xu
authors.affiliation: Department of Ophthalmology, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, MD.
authors.forename: Yuri V
authors.initials: YV
authors.lastname: Sergeev
authors.affiliation: Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China.
authors.forename: Ruifang
authors.initials: R
authors.lastname: Sui
mesh_terms: D000328:Adult; D000792:Angiography; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D002681:China; D004479:Ectopia Lentis / Q000000981:diagnostic imaging / Q000235:genetics*; D005190:Family; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D005799:Genes, Dominant; D008040:Genetic Linkage; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D012501:Saphenous Vein / Q000000981:diagnostic imaging / Q000473:pathology*; D017422:Sequence Analysis, DNA; D014648:Varicose Veins / Q000235:genetics* / Q000473:pathology; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines