Thesis (Ph. D.)--Ruhr-Universität Bochum, 1978. / "Mit einem vollständigen bibliographischen Verzeichnis von Uwe-Michael Gutzschhahn und Wulf Segebrecht." Includes bibliographical references (p. 381-422).

Meckel-Gruber syndrome (MKS) is a universally lethal heritable human disease characterised by CNS malformations, cystic kidney, polydactyly, and liver fibrosis. MKS is classed as one of the ciliopathies due to its association with dysfunctional primary cilia, signalling organelles found on most cells in the human body. Some of the symptoms of MKS can be explained as a consequence of disrupted developmental signalling through the primary cilium, other defects are harder to explain, and evidence now exists for non-ciliary influences on ciliopathies. The nature of these influences, and the implications they may have for our understanding of ciliary function and the aetiology of MKS, remain unclear. In this thesis, defects in cell-extracellular matrix (ECM) interaction in MKS are investigated to determine whether MKS proteins have a role in this process, and if so, whether this role may be involved in MKS pathology. A combination of transcriptomic, proteomic, and cell imaging approaches are used to demonstrate that MKS patient cells produce a defective extracellular matrix, and that the MKS protein TMEM67 is present at the cell surface at sites of cell-ECM interaction. It is shown that the full-length TMEM67 protein is required for correct ECM morphology, and it is further shown that the abnormal extracellular matrix morphology in MKS cells underlies other defects, including failure to build cilia and alterations to the actin cytoskeleton. This represents the first set of causal relationships identified between the cellular defects in this complex disease. It is further shown that treatment with developmental signalling pathway antagonists can rescue these defects, potentially revealing a new avenue of therapeutic intervention for MKS. Finally, possible upstream defects are investigated that might underlie the ECM defect, including alterations to cell spreading behaviour and cell deformation resistance.