Prenatal sonographic assessment and perinatal course of ichthyosis prematurity syndrome.

All cases of ichthyosis prematurity syndrome (IPS), registered at the National Center for Fetal Medicine in Trondheim, Norway between 1987 and 2010 were identified and the findings analyzed. Five fetuses with IPS were identified between 1988 and 2000. All five developed polyhydramnios between 28 and 31 weeks. The fetal stomach appeared to be empty in four cases, and was not described in one case. The fetal skin was described as 'uneven' at ultrasound examination in two cases. Separation of chorionic and amniotic membranes with a peculiar appearance of echo-free fluid in the chorionic cavity and echogenic sediment in the amniotic cavity were observed between 28 + 5 and 32 + 3 weeks in all cases. All fetuses were delivered prematurely between 30 and 34 weeks. All neonates had difficulties in breathing, two developed aspiration pneumonia, and one had bilateral pneumothorax after intubation and died at 6 months because of pulmonary and cardiac sequelae. Prenatal sonographic signs of IPS are separation of the membranes, echogenic amniotic fluid and echo-free chorionic fluid occurring between 28 and 32 weeks' gestation. Delivery occurs at 30-34 weeks and, as there is a high risk of asphyxia, an experienced neonatal intensive care unit team should be present at delivery.

Modulation of intracellular transport of acidic fibroblast growth factor by mutations in the cytoplasmic receptor domain.

Endocytic uptake and intracellular transport of acidic fibroblast growth factor (aFGF) was studied in cells transfected with FGF receptor 4 with mutations in the cytoplasmic part. Endocytic uptake in HeLa cells was reduced but not abolished when the tyrosine kinase of the receptor was inactivated by mutations or deletions. The tyrosine kinase-dependent endocytosis of aFGF was prevented by the expression of a dominant negative dynamin mutant that blocks endocytosis from coated pits and caveolae. However, more than half of the total endocytic uptake of aFGF was not affected under these conditions, indicating an endocytic uptake mechanism not involving coated pits or caveolae. Mutation or deletion of a putative caveolin-binding sequence did not prevent the localization of part of the receptors to a low density, caveolin-containing subcellular fraction. Whereas wild-type receptor transfers the growth factor from early endosomes to the recycling compartment, kinase negative, full length receptors were inefficient in this respect and the growth factor instead accumulated in lysosomes. By contrast, when most of the intracellular part of the receptor, including the kinase domain, was removed, aFGF was transported to the recycling compartment, as in cells that express wild-type receptors, suggesting the presence of a kinase-regulated targeting signal in the cytoplasmic tail.

Requirement for C-terminal end of fibroblast growth factor receptor 4 in translocation of acidic fibroblast growth factor to cytosol and nucleus.

The ability of COS cells to bind and internalise acidic fibroblast growth factor (aFGF) was studied after transient transfection of the cells with wild-type and mutated fibroblast growth factor receptor 4. In one case the tyrosine kinase of the receptor was inactivated by a point mutation in the active site, whereas in other cases parts of the receptor were deleted to remove various parts of the cytoplasmic domain. In all cases the receptors were expressed at the cell surface at a high level and the cells bound labelled growth factor efficiently and internalised it by endocytosis. Translocation of externally added aFGF across cellular membranes to reach the cytosol and nucleus was measured as transport of labelled growth factor to the nuclear fraction obtained by centrifugation, by farnesylation of growth factor modified to carry a CAAX motif, and by phosphorylation of the growth factor at a site specific for protein kinase C. Whereas both full-length receptors (with and without an active kinase domain) facilitated translocation of the growth factor to the cytosol and nucleus, as assessed by these methods, the mutants of the receptor where the C terminus was deleted, were unable to do so. In contrast, a receptor containing only the 57 most C-terminal amino acids of the cytoplasmic domain in addition to the juxtamembrane, transmembrane and extracellular domains, was in fact able to mediate translocation of aFGF to the cytosol. These data indicate that information contained in the C terminus of the receptor is required for translocation.