Mutation screening of complete fibrillin-1 coding sequence: report of five new mutations, including two in 8-cysteine domains.
Marfan syndrome (MFS) is an autosomal dominantly inherited connective tissue disorder characterized by cardiovascular, ocular and skeletal manifestations. Previously, mutations in the fibrillin-1 gene on chromosome 15 (FBN1) have been reported to cause MFS. We have now screened 44 probands with MFS or related phenotypes for alterations in the entire fibrillin coding sequence (9.3 kb) by single strand conformation analysis. We report four unique mutations in the fibrillin gene of unrelated MFS patients. One is a 17 bp deletion and three are missense mutations, two of which involve 8-cysteine motifs. Another missense mutation was found in two unrelated individuals with annuloaortic ectasia but was also present in unaffected relatives and controls from various ethnic backgrounds. By using allele-specific oligonucleotide hybridization, we screened 65 unrelated MFS patients, 29 patients with related phenotypes and 84 control individuals for these mutations as well as for a previously reported mutation and two polymorphisms. Our results suggest that most MFS families carry unique mutations and that the fibrillin genotype is not the sole determinant of the connective tissue phenotype.
Tynan
K
K
Howard Hughes Medical Institute, Stanford University Medical Center, CA 94305.
Comeau
K
K
Pearson
M
M
Wilgenbus
P
P
Levitt
D
D
Gasner
C
C
Berg
M A
MA
Miller
D C
DC
Francke
U
U
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15; D016384:Consensus Sequence; D003545:Cysteine; D017931:DNA Primers; D005190:Family; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D005799:Genes, Dominant; D006801:Humans; D007438:Introns; D008297:Male; D008382:Marfan Syndrome / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D017384:Sequence Deletion; D012867:Skin / Q000378:metabolism; D054392:Adipokines
D003545:Cysteine; D017931:DNA Primers; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines