In the absence of any family history, the presence of these two manifestations is sufficient for the unequivocal diagnosis of MFS. In absence of either of these two, the presence of a bonafide FBN1 mutation or a combination of systemic manifestations is required. For the latter a new scoring system has been designed. In this revised nosology, FBN1 testing, although not mandatory, has greater weight in the diagnostic assessment. Special considerations are given to the diagnosis of MFS in children and alternative diagnoses in adults. We anticipate that these new guidelines may delay a definitive diagnosis of MFS but will decrease the risk of premature or misdiagnosis and facilitate worldwide discussion of risk and follow-up/management guidelines.

Aortic aneurysm and dissection are manifestations of Marfan syndrome (MFS), a disorder caused by mutations in the gene that encodes fibrillin-1. Selected manifestations of MFS reflect excessive signaling by the transforming growth factor-β (TGF-β) family of cytokines. We show that aortic aneurysm in a mouse model of MFS is associated with increased TGF-β signaling and can be prevented by TGF-β antagonists such as TGF-β-neutralizing antibody or the angiotensin II type 1 receptor (AT1) blocker, losartan. AT1 antagonism also partially reversed noncardiovascular manifestations of MFS, including impaired alveolar septation. These data suggest that losartan, a drug already in clinical use for hypertension, merits investigation as a therapeutic strategy for patients with MFS and has the potential to prevent the major life-threatening manifestation of this disorder.MFS is a systemic disorder of connective tissue caused by mutations in FBN1, the gene encoding fibrillin-1 (1). As a principal component of the extracellular matrix microfibril (2, 3), fibrillin-1 was initially thought to play primarily a structural role in connective tissue. Several lines of evidence support an additional role as a regulator of the cytokine TGF-β (4, 5). Mice homozygous for a hypomorphic Fbn1 allele have impaired pulmonary alveolar septation associated with increased TGF-β signaling that can be prevented by perinatal administration of a polyclonal TGF-β neutralizing antibody (NAb) (5). Similarly, myxomatous

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Marfan syndrome is an autosomal dominant disorder of connective tissue caused by mutations in fibrillin-1 (encoded by FBN1 in humans and Fbn1 in mice), a matrix component of extracellular microfibrils. A distinct subgroup of individuals with Marfan syndrome have distal airspace enlargement, historically described as emphysema, which frequently results in spontaneous lung rupture (pneumothorax; refs. 1-3). To investigate the pathogenesis of genetically imposed emphysema, we analyzed the lung phenotype of mice deficient in fibrillin-1, an accepted model of Marfan syndrome. Lung abnormalities are evident in the immediate postnatal period and manifest as a developmental impairment of distal alveolar septation. Aged mice deficient in fibrillin-1 develop destructive emphysema consistent with the view that early developmental perturbations can predispose to late-onset, seemingly acquired phenotypes. We show that mice deficient in fibrillin-1 have marked dysregulation of transforming growth factor-beta (TGF-beta) activation and signaling, resulting in apoptosis in the developing lung. Perinatal antagonism of TGF-beta attenuates apoptosis and rescues alveolar septation in vivo. These data indicate that matrix sequestration of cytokines is crucial to their regulated activation and signaling and that perturbation of this function can contribute to the pathogenesis of disease.

Marfan syndrome is an inherited disorder of connective tissue manifested in the ocular, skeletal and cardiovascular systems. It is inherited as an autosomal dominant with high penetrance, but has great clinical variability. Linkage studies have mapped the Marfan locus to chromosome 15q15-21.3. There have been no reports of genetic heterogeneity in the syndrome. Following the identification of fibrillin (a glycoprotein component of the extracellular microfibril), immunohistopathological quantification of the protein in skin and fibroblast culture, and examination of fibrillin synthesis, extracellular transport, and incorporation into the extracellular matrix (D. M. Milewicz, R.E.P., E. S. Crawford and P. H. Byers, manuscript in preparation) have demonstrated abnormalities of fibrillin metabolism in most patients. A portion of the complementary DNA encoding fibrillin has been cloned and mapped by in situ hybridization to chromosome 15. Here we report that the fibrillin gene is linked to the Marfan phenotype (theta = 0.00; logarithm of the odds (lod) = 3.9) and describe a de novo missense mutation in the fibrillin gene in two patients with sporadic disease. We thus implicate fibrillin as the protein defective in patients with the Marfan syndrome.

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Marfan's syndrome is a systemic disorder of connective tissue caused by mutations in the extracellular matrix protein fibrillin 1. Cardinal manifestations include proximal aortic aneurysm, dislocation of the ocular lens, and long-bone overgrowth. Important advances have been made in the diagnosis and medical and surgical care of affected individuals, yet substantial morbidity and premature mortality remain associated with this disorder. Progress has been made with genetically defined mouse models to elucidate the pathogenetic sequence that is initiated by fibrillin-1 deficiency. The new understanding is that many aspects of the disease are caused by altered regulation of transforming growth factor beta (TGFbeta), a family of cytokines that affect cellular performance, highlighting the potential therapeutic application of TGFbeta antagonists. Insights derived from studying this mendelian disorder are anticipated to have relevance for more common and non-syndromic presentations of selected aspects of the Marfan phenotype.

All eukaryotes possess the ability to detect and degrade transcripts harboring premature signals for the termination of translation. Despite the ubiquitous nature of nonsense-mediated mRNA decay (NMD) and its demonstrated role in the modulation of phenotypes resulting from selected nonsense alleles, very little is known regarding its basic mechanism or the selective pressure for complete evolutionary conservation of this function. This review will present the current models of NMD that have been generated during the study of model organisms and mammalian cells. The physiological burden of nonsense transcripts and the emerging view that NMD plays a broad and critical role in the regulation of gene expression will also be discussed. Such issues are relevant to the proposal that pharmacological manipulation of NMD will find therapeutic application.