ABSTRACT
Meckel syndrome (MKS) is a lethal malformation syndrome characterised by posterior meningoencephalocele, polycystic kidneys, fibrotic changes of the liver, and polydactyly. We have previously shown a linkage to chromosome 17q in 17 Finnish Meckel families. In this study we have analysed one Italian, one Austrian (of Turkish origin) and three British MKS families (Caucasian, Pakistani, and Bangladeshi families) for linkage to the MKS locus on chromosome 17q22-q24. We did not observe co-segregation of the disease and marker haplotypes in the Austrian family or in the three British families, of which two represented classical MKS and one a slightly atypical MKS phenotype with longer survival of the patient. In the Italian family the affected and non-affected children did not share the same maternal chromosome and thus this family could represent the same allelic disease as the Finnish MKS families. These results suggest locus heterogeneity in Meckel syndrome--a feature previously suspected based on the highly variable clinical phenotype.
Subject(s)
Abnormalities, Multiple/genetics , Abnormalities, Multiple/pathology , Alleles , DNA/genetics , Female , Genetic Linkage , Humans , Infant, Newborn , Liver Cirrhosis/genetics , Lod Score , Male , Neural Tube Defects/genetics , Pedigree , Phenotype , Polycystic Kidney Diseases/genetics , Polydactyly/genetics , Pregnancy , SyndromeABSTRACT
An elevation of the intracellular pH and a rise in the cytoplasmic Ca2+ concentration are considered important mitogenic signals which are observed after stimulation by various growth factors. In a preceding report it was demonstrated that the expression of Ha-ras or v-mos in cells transfected with Ha-ras or v-mos, respectively, leads to an activation of the Na+/H+ antiporter and a concomitant rise in intracellular pH (W. Doppler, R. Jaggi, and B. Groner, Gene 54:145-151, 1987). This report describes the effect of the Ha-ras and v-mos oncogenes on intracellular Ca2+ release. The expression of Ha-ras in NIH 3T3 cells carrying a glucocorticoid-inducible transforming Ha-ras gene caused a desensitization of the Ca2+-mobilizing system to serum growth factors. The induction of p21ras in cells carrying the corresponding glucocorticoid-inducible proto-oncogene did not affect the Ca2+ response to growth factors. Conditions leading to the expression of the transforming Ha-ras gene but not those causing the induction of the normal Ha-ras gene yielded an increase in phosphatidylinositol turnover and a concomitant rise in inositol phosphates. Results similar to those obtained with the transforming Ha-ras gene were seen after the expression of v-mos. The data are consistent with a mechanism in which expression of the transforming Ha-ras gene leads to a release of Ca2+ from intracellular stores via elevated levels of inositol trisphosphate.
