Mutations in the gene coding for fibrillin on chromosome 15 (FBN1) are known to cause Marfan syndrome (MFS). A related disorder, dominant ectopia lentis (EL), has also been linked genetically to this locus. We now describe ten novel mutations of FBN1 resulting in strikingly different phenotypes. In addition to classic MFS, FBN1 mutations also give rise to EL and a severe neonatal form of MFS. Interestingly, the neonatal MFS mutations are clustered in one particular region of FBN1, possibly providing new insights into genotype-phenotype comparisons.

Venous malformations (VMs) are localized defects of vascular morphogenesis. They can occur in every organ system, most commonly in skin and muscle. They can cause pain and bleeding, and in some critical locations they can be life threatening. Usually venous anomalies occur sporadically, but families with dominant inheritance have been identified. Using linkage analysis, we have established in earlier reports that some families with inherited VMs show linkage to chromosome 9p21; the mutation causes ligand-independent activation of an endothelial cell-specific receptor tyrosine kinase, TIE-2. Here we show that VMs with glomus cells (known as "glomangiomas"), inherited as an autosomal dominant trait in five families, are not linked to 9p21 but, instead, link to a new locus, on 1p21-p22, called "VMGLOM" (LOD score 12.70 at recombination fraction.00). We exclude three known positional candidate genes, DR1 (depressor of transcription 1), TGFBR3 (transforming growth factor-beta receptor, type 3), and TFA (tissue factor). We hypothesize that cutaneous venous anomalies (i.e., glomangiomas) are caused by mutations in a novel gene that may act to regulate angiogenesis, in concert with the TIE-2 signaling pathway.

No abstract

Fibrillin is the major component of extracellular microfibrils. Mutations in the fibrillin gene on chromosome 15 (FBN1) were described at first in the heritable connective tissue disorder, Marfan syndrome (MFS). More recently, FBN1 has also been shown to harbor mutations related to a spectrum of conditions phenotypically related to MFS. These mutations are private, essentially missense, generally non-recurrent and widely distributed throughout the gene. To date no clear genotype/phenotype relationship has been observed excepted for the localization of neonatal mutations in a cluster between exons 24 and 32. The second version of the computerized Marfan database contains 89 entries. The software has been modified to accomodate new functions and routines.

We introduce here a novel and generally applicable, solid-phase minisequencing-based approach for rapid estimation of relative levels of transcripts with high sequence homology. This study was undertaken to screen for the consequences of different fibrillin-I mutations on the transcript levels in patients with the Marfan syndrome (MFS). This dominantly inherited, connective tissue disorder is characterized by pleiotrophic symptoms in cardiovascular, skeletal, and ocular systems. A spectrum of disease mutations in the gene encoding fibrillin-1 (FBNI), a glycoprotein component of extracellular matrix microfibrils, has been identified in MFS patients, but the mechanisms by which mutations result in different phenotypic manifestations are still unknown to a large extent. Our data from the quantitation of FBN1 transcripts provide support for the hypothesis that mutations causing premature stop codons result in a milder phenotype than classical MFS by reducing the stability of the mutant transcript and, consequently, decreasing the interference of mutant polypeptide in the formation of fibrillin fibers. We also applied this mRNA quantitation method to determine the relative ratio between transcripts from the genes coding for two highly homologous microfibrillar components, FBN1 and FBN2, in control fibroblast cultures as well as in fibroblasts from MFS patients. Interestingly, these data show large variations between the levels of the two transcripts in fibroblast cultures, but these variations do not correlate either with the nature of the disease mutation or to the clinical MFS phenotype.