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The American Journal of Human Genetics published in 2009 four cases of newborn children with a complex disease pattern, the Urban-Rifkin-Davis Syndrome (URDS). All patients had mutations of the Latent TGF¬β binding Protein 4 (LTBP¬4) gene. LTBP¬4 is one of four known LTB proteins. Eponymous for this protein family is the strong interaction with Transforming growth factor β (TGF¬β). In addition LTBP¬4 it is assumed as a distinct structural protein of the ECM.
Disruption of LTBP¬4 leads to a variety of disease patterns. Preceding studies have shown that mice lacking the short variant of Ltbp¬4 (Ltbp4s) develop a complex phenotype with cardiomyopathy, colorectal cancer and pulmonary emphysema. Human patients suffering URDS exhibit impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal and dermal development. Despite a huge variety of disease patterns all individuals with mutations in the LTBP¬4 gene share one phenotype; the development of pulmonary emphysema at the stage of postnatal alveolarisation.
Aim of this study was the structural and functional analysis of LTBP¬4 as a factor of pathogenesis in the development of pulmonary emphysema.
To avoid any splicevariant specific effects, Ltbp4 complete knockout mice (Ltbp4-/-) were analysed via assessment of oxygenation and lung structure. In vitro investigations on myofibroblast transdifferentation, matrix structuration and TGFβ activation were performed on primary murine Ltbp4-/- lung fibroblasts as well as siRNA transfected, LTBP4 deficient human lung fibroblasts.
Ltbp4-/- mice die within the first ten days of life with severe hypercapnia and polycythemia. Lung tissue of Ltbp4-/- mice exhibit impaired alveolarisation, disrupted alveolar elastic fibre distribution and reduced myofibroblast transdifferentation. Both primary Ltbp4-/- lung fibroblasts as well as siRNA transfected, LTBP4 deficient human lung fibroblasts revealed impaired matrix structuration in vitro.
In summary two key processes of postnatal alveolarisation: myofibroblast transdifferentation and alveolar elastic fibre formation are disrupted in Ltbp4-/- mice, thereby implicating the pivotal role of LTBP4 during alveolarisation. This is the first study investigating the impact of Ltbp¬4 on postnatal alveolarisation by means of a new animal model, the Ltbp4-/- model.