Four novel FBN1 mutations: Significance for mutant transcript level and EGF-like domain calcium binding in the pathogenesis of Marfan syndrome

Journal Article · Sun Aug 01 04:00:00 EDT 1993 · Genomics; (United States)

DOI:https://doi.org/10.1006/geno.1993.1349· OSTI ID:7225730

Dietz, H C; McIntosh, I; Pyeritz, R E; Francomano, C A ^[1]; Sakai, L Y; Corson, G M; Chalberg, S C ^[2]

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1. Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States)
2. Oregon Health Sciences Univ., Portland (United States)

Defects of fibrillin (FBN1), a glycoprotein component of the extracellular microfibril, cause Marfan syndrome. This disorder is characterized by marked inter- and intrafamilial variation in phenotypic severity. To understand the molecular basis for this clinical observation, the authors have screened the fibrillin gene (FBN1) on chromosome 15, including the newly cloned 5[prime] coding sequence, for disease-producing alterations in a panel of patients with a wide range of manifestations and clinical severity. All the missense mutations identified to date, including two novel mutations discussed here, are associated with classic and moderate to severe disease and occur at residues with putative significance for calcium binding to epidermal growth factor (EGF)-like domains. In contrast, two new mutations that create premature signals for termination of translation of mRNA and are associated with reduction in the amount of mutant allele transcript produce a range of phenotypic severity. The patient with the lowest amount of mutant transcript has the mildest disease. These data support a role for altered calcium binding to EGF-like domains in the pathogenesis of Marfan syndrome and suggest a dominant negative mechanism for the pathogenesis of this disorder. 26 refs., 6 figs., 1 tab.

• OSTI ID: 7225730
• Journal Information: Genomics; (United States), Journal Name: Genomics; (United States) Vol. 17:2; ISSN 0888-7543; ISSN GNMCEP
• Country of Publication: United States
• Language: English

Related Subjects

550400* -- Genetics
550900 -- Pathology
59 BASIC BIOLOGICAL SCIENCES
ANIMALS
BODY
BODY AREAS
CARDIOVASCULAR DISEASES
DISEASES
EYES
FACE
GENE MUTATIONS
GLYCOPROTEINS
GROWTH
HEAD
HEREDITARY DISEASES
MAMMALS
MAN
MUTATIONS
ORGANIC COMPOUNDS
ORGANS
PATHOGENESIS
PRIMATES
PROTEINS
SENSE ORGANS
SKELETAL DISEASES
VERTEBRATES