Nature Genetics
- 33, 407 - 411 (2003)
Published online: 24 February 2003; | doi:10.1038/ng1116
Dysregulation of TGF- activation contributes to pathogenesis in Marfan syndromeEnid R. Neptune1, 2, Pamela A. Frischmeyer2, Dan E. Arking2, Loretha Myers2, Tracie E. Bunton3, Barbara Gayraud4, Francesco Ramirez4, Lynn Y. Sakai5 & Harry C. Dietz2, 61
Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. 2
Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. 3
Department of Safety Assessment, Dupont Phamaceuticals Company, Newark, Delaware 19714, USA. 4
Hospital for Special Surgery, New York, New York 10021, USA. 5
Shriners Hospital, Portland, Oregon 97201, USA. 6
Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Correspondence should be addressed to Harry C. Dietz hdietz@jhmi.edu 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 syndrome4. 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- (TGF-) activation and signaling, resulting in apoptosis in the developing lung. Perinatal antagonism of TGF- 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.
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