Search

Background We describe two unrelated patients who display similar clinical features including telangiectasia, ectodermal dysplasia, brachydactyly and congenital heart disease. Methods We performed trio whole exome sequencing and functional analysis using in vitro kinase assays with recombinant proteins. Results We identified two different de novo mutations in protein kinase D1 (PRKD1, NM_002742.2): c.1774G>C, p.(Gly592Arg) and c.1808G>A, p.(Arg603His), one in each patient. PRKD1 (PKD1, HGNC:9407) encodes a kinase that is a member of the protein kinase D (PKD) family of serine/threonine protein kinases involved in diverse cellular processes such as cell differentiation and proliferation and cell migration as well as vesicle transport and angiogenesis. Functional analysis using in vitro kinase assays with recombinant proteins showed that the mutation c.1808G>A, p.(Arg603His) represents a gain-of-function mutation encoding an enzyme with a constitutive, lipid-independent catalytic activity. The mutation c.1774G>C, p.(Gly592Arg) in contrast shows a defect in substrate phosphorylation representing a loss-of-function mutation. Conclusion The present cases represent a syndrome, which associates symptoms from several different organ systems: skin, teeth, bones and heart, caused by heterozygous de novo mutations in PRKD1 and expands the clinical spectrum of PRKD1 mutations, which have hitherto been linked to syndromic congenital heart disease and limb abnormalities. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC), mostly the result of chronic liver diseases, is ranked as the fifth most common cancer world-wide. To find new treatments, a better understanding of the initiation, the progression and the implication of the cellular metabolism in the development of HCC is needed. Hypoxia and IL6-type cytokines can promote tumour growth, influence cellular metabolism and prevent cancer cells from apoptosis [1] . Furthermore, IL6-type cytokines induce the expression of HIF-1 α , one of the key mediators of the cellular response to hypoxia [2] . Constitutively active STAT3 leads to an increased production of lactate under normoxic conditions. This effect was HIF-1 α -dependent [3] . We investigated the effects of the IL6-type cytokine Oncostatin M (OSM) on hepatocytes and HCC cell lines under normoxia. Quantitative real-time PCR and quantitative WB analysis was performed focusing on the regulation of glycolytic enzymes, many being direct HIF-1 α target genes. Contrary to the HCC lines, in non-neoplastic PH5CH8 hepatocytes an OSM-mediated induction of pyruvate dehydrogenase kinase 1 (PDK1) was found together with an increase in the pyruvate dehydrogenase (PDH) phosphorylation level, indicating that these cells shift to a more glycolytic metabolism. Metabolic analysis is being carried out to validate this finding. We found little OSM effects under normoxia on the induction of glycolytic enzymes (mRNA and protein level). Surprisingly, even hypoxic treatment only affected few genes previously described to be HIF-1 α targets. Funded by the University of Luxembourg Tandem project “Meta-IL6”. [ABSTRACT FROM AUTHOR]