Explore the vast range of titles available.

BackgroundWe describe two unrelated patients who display similar clinical features including telangiectasia, ectodermal dysplasia, brachydactyly and congenital heart disease.MethodsWe performed trio whole exome sequencing and functional analysis using in vitro kinase assays with recombinant proteins.ResultsWe 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.ConclusionThe 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.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterised by vascular dysplasia and increased bleeding that affect 1 in 5,000 people world-wide. Pathology is linked to mutations in genes encoding components of the heteromeric transforming growth factor-beta receptor (TGF-beta) and SMAD signalling pathway. Indeed HHT1 and HHT2 result from mutations in the genes encoding endoglin and activin-like kinase 1 (ALK1), TGF-beta receptor components. However, the fundamental cellular defects underlying HHT is poorly understood. Previously using confocal microscopy and N -glycosylation analysis, we found evidence that defective trafficking of endoglin from the endoplasmic reticulum (ER) to the plasma membrane is a mechanism underlying HHT1 in some patients. In this study, we used confocal microscopy to investigate whether a similar mechanism contributes to HHT2 pathology. To do this we expressed wild-type ALK1 and a number of HHT2 patient mutant variants as C-terminally tagged EGFP fusion proteins and tested their localisation in HeLa cells. We found that wild-type ALK1–EGFP was targeted predominantly to the plasma membrane, as evidenced by its colocalisation with the co-expressed HA-tagged endoglin. However, we found that in the majority of cases analysed the HHT2 patient mutant protein was retained within the ER as indicated by their colocalisation with the ER resident marker (calnexin) and lack of colocalisation with cell surface associated HA-endoglin. We conclude that defective trafficking and retention in the ER of mutant ALK1 protein is a possible mechanism of HHT2 in some patients.

Health status of feral Nile tilapia following repeated applications of fenthion as a mosquito larvicide to selected water canals in Sri Lanka was assessed. With three spray applications of fenthion to the study sites at weekly intervals at the concentration recommended for mosquito control, condition factor and brain acetylcholinesterase activity of the fish were depressed in a time dependent manner. Prominent histopathological alterations displayed were gill hyperplasia and telangiectasis and vacoulation of hepatocytes. Observed ill health effects of fenthion on the fish demonstrate probable ecological risk to the fish populations inhabiting the water canals which receive repeated inputs of fenthion.