Mouse Genome Informatics
hm
    Fbn1tm1Rmz/Fbn1tm1Rmz
involves: 129S4/SvJae * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
mortality/aging
• all die suddenly of cardiovascular complications before weaning age (J:43199)
• mice die at P7-P10 from aortic dissection and rupture (J:91815)

cardiovascular system
• 6 of 9 show thinning of the wall of the proximal ascending aorta, suggesting aneurismal dilation
• exhibit focal fragmentation of elastic fibers, accumulation of amorphous matrix and dissection of blood into the aortic media (aortic dissection)
• chronic lesions in the aorta show expansion of the intramural thrombus, recruitment of inflammatory cells and an adventitial reaction of cellular proliferation when the full thinckness of the wall is breached
• 6 of 9 show thinning of the wall of the proximal ascending aorta, suggesting aneurismal dilation
• 6 of 9 exhibit dissection of blood into the aortic media (aortic dissection)
• pulmonary vessels occasionally appear distended and hyalinized
• pulmonary hemorrhage

respiratory system
• pulmonary vessels occasionally appear distended and hyalinized
• pulmonary hemorrhage
• mice exhibit enhanced TGF-beta signaling and impaired distal airspace septation
• at P7, dysregulation of TGF-beta activation and signaling results in increased apoptosis, but normal cell proliferation, in the developing lung
• treatment with TGF-beta neutralizing antibody attenuates apoptosis and improves alveolar septation in vivo
• proximal airway caliber and vasculature are grossly normal
• no differences in airway cell differentiation or elastin deposition are observed
• at P9, rare secondary alveolar septae are observed, indicating impaired distal alveolar septation (J:91815)
• active TGF-beta signaling is enhanced in mutant lungs by a factor of 25 relative to wild-type controls; neutralizing antibody to TGF-beta rescues the lung maturation phenotype, suggesting that TGF-beta is a physiologic inhibitor of alveolar septation (J:91815)
• at P5, expression of NeuroD1 protein (a candidate septation mediator) is reduced by 5-fold relative to that in wild-type controls; treatment with TGF-beta neutralizing antibody causes only a 1.5-fold induction of NeuroD1 expression , suggesting a minor contribution of NeuroD1 deficiency to the lung phenotype (J:137934)
• at P5, the average size of mutant pulmonary NEBs is ~30% smaller than that in wild-type mice, suggesting impaired neuroendocrine maturation
• at P5, the total number of pulmonary neuroendocrine foci (composed of NEBs and PNECs) is modestly higher than that of wild-type controls
• mice occasionally exhibit multifocal distension and coalescence of alveoli
• mice display progressive distal airspace enlargement, apparent from P1 (J:91815)
• at P5, distal airspaces are enlarged, as shown by a significant increase in mean linear intercept (J:137934)
• the airspace lesion is progressive throughout postnatal life (J:137934)
• at P9, rare secondary alveolar septae are observed (J:91815)
• alveolar septation is impaired in the immediate postnatal period (J:137934)
• mice occasionally exhibit multifocal distension and coalescence of alveoli suggesting emphysema

homeostasis/metabolism
• exhibit thrombosis of the aortic wall

endocrine/exocrine glands
• at P5, the total number of pulmonary neuroendocrine foci (composed of NEBs and PNECs) is modestly higher than that of wild-type controls

nervous system
• at P5, the total number of pulmonary neuroendocrine foci (composed of NEBs and PNECs) is modestly higher than that of wild-type controls

Mouse Models of Human Disease
OMIM IDRef(s)
Marfan Syndrome; MFS 154700 J:43199