A Founder Mutation in Presents with Tubular Proteinuria and Deafness.

Background: The endocytic reabsorption of proteins in the proximal tubule requires a complex machinery and defects can lead to tubular proteinuria. The precise mechanisms of endocytosis and processing of receptors and cargo are incompletely understood. EHD1 belongs to a family of proteins presumably involved in the scission of intracellular vesicles and in ciliogenesis.

Quantification of FAM20A in human milk and identification of calcium metabolism proteins.

Background: FAM20A, a recently discovered protein, is thought to have a fundamental role in inhibiting ectopic calcification. Several studies have demonstrated that variants of FAM20A are causative for the rare autosomal recessive disorder, enamel-renal syndrome (ERS). ERS is characterized by defective mineralization of dental enamel and nephrocalcinosis suggesting that FAM20A is an extracellular matrix protein, dysfunction of which causes calcification of the secretory epithelial tissues.

Glycine Amidinotransferase (GATM), Renal Fanconi Syndrome, and Kidney Failure.

For many patients with kidney failure, the cause and underlying defect remain unknown. Here, we describe a novel mechanism of a genetic order characterized by renal Fanconi syndrome and kidney failure. We clinically and genetically characterized members of five families with autosomal dominant renal Fanconi syndrome and kidney failure.

Cyclophosphamide and rituximab in frequently relapsing/steroid-dependent nephrotic syndrome.

Background: Steroid-sensitive nephrotic syndrome is the most common form of nephrotic syndrome in childhood, defined by the response to treatment with glucocorticoids with consequent remission. While most children eventually experience spontaneous resolution of the disease, some have a difficult course with frequent relapses or steroid dependence nephrotic syndrome (FRSDNS). The consequent steroid toxicity often prompts administration of other immunosuppressive drugs, traditionally cyclophosphamide.

HNF1B-associated clinical phenotypes: the kidney and beyond.

Mutations in HNF1B, the gene encoding hepatocyte nuclear factor 1β are the most commonly identified genetic cause of renal malformations. HNF1B was first identified as a disease gene for diabetes (MODY5) in 1997, and its involvement in renal disease was subsequently noted through clinical observations in pedigrees affected by MODY5. Since then, a whole spectrum of associated phenotypes have been reported, including genital malformations, autism, epilepsy, gout, hypomagnesaemia, primary hyperparathyroidism, liver and intestinal abnormalities and a rare form of kidney cancer.

Mistargeting of peroxisomal EHHADH and inherited renal Fanconi's syndrome.

Background: In renal Fanconi's syndrome, dysfunction in proximal tubular cells leads to renal losses of water, electrolytes, and low-molecular-weight nutrients. For most types of isolated Fanconi's syndrome, the genetic cause and underlying defect remain unknown.

Methods: We clinically and genetically characterized members of a five-generation black family with isolated autosomal dominant Fanconi's syndrome.

Nephrocalcinosis (enamel renal syndrome) caused by autosomal recessive FAM20A mutations.

Background/aims: Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood.

Methods: We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption).

Renal FMD may not confer a familial hypertensive risk nor is it caused by ACTA2 mutations.

Renal fibromuscular dysplasia (FMD) can cause hypertension, and previous reports suggest that FMD is familial. We hypothesized that, in families containing an individual with proven FMD, relatives of index cases would have an increased risk of hypertension. ACTA2 mutations cause a spectrum of extra-renal arteriopathy, leading to our second hypothesis that mutations are implicated in FMD.

Hereditary hypophosphatemic rickets with hypercalciuria and nephrolithiasis-identification of a novel SLC34A3/NaPi-IIc mutation.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is characterized by rickets, hyperphosphaturia, hypophosphatemia, elevated 1,25-dihydroxyvitamin-D, increased gastrointestinal calcium absorption and hypercalciuria. Serum calcium, 25-hydroxyvitamin-D and PTH levels are normal. Here we describe a boy with HHRH, nephrolithiasis, and compound heterozygosity for one previously described mutation (g.

A patient with hypophosphatemia, a femoral fracture, and recurrent kidney stones: report of a novel mutation in SLC34A3.

Objective: To determine if there was a genetic contribution to our patient's unusual clinical presentation of nephrolithiasis and nonhealing stress fracture.

Methods: We describe a 31-year-old man who had rickets as a child and developed a femur insufficiency fracture and recurrent nephrolithiasis as an adult after moving to the United States from India. The patient's clinical course and results from radiographic and biochemical analyses are described.

A novel missense mutation in SLC34A3 that causes hereditary hypophosphatemic rickets with hypercalciuria in humans identifies threonine 137 as an important determinant of sodium-phosphate cotransport in NaPi-IIc.

The present study describes two novel compound heterozygous mutations, c.410C>T(p.T137M) (T137M) on the maternal and g.

Plasmodium falciparum: functional mitochondrial ADP/ATP transporter in Escherichia coli plasmic membrane as a tool for selective drug screening.

Plasmodium falciparum mitochondrial ADP/ATP transporter or adenylate translocase (PfAdT) was previously characterised at the molecular level and intracellularly located by immuno-electromicroscopy. Inhibition of this transporter blocks parasite development in erythrocytes. In this study, PfAdT was expressed in C43 (DE3) Escherichia coli strain under isopropyl beta-d-thiogalacto-pyranoside (IPTG) induction to screen inhibitory molecules.

Wedelolides A and B: novel sesquiterpene delta-lactones, (9R)-eudesman-9,12-olides, from Wedelia trilobata.

Two new sesquiterpene lactones, wedelolides A (1) and B (2), were isolated by bioassay-guided fractionation from the leaves of Wedelia trilobata, together with known trilobolides 6-O-isobutyrate (3) and 6-O-methacrylate (4). The compounds 1 and 2 were the first examples of an unprecedented framework: a novel sesquiterpene delta-lactone, (9R)-eudesman-9,12-olide. The structures of the antimalarial wedelolides A (1) and B (2) were determined on the basis of MS and 2D NMR spectral analysis.

Antiplasmodial activity of acetogenins and inhibitory effect on Plasmodium falciparum adenylate translocase.

Three Annonaceous acetogenins exhibited in vitro antimalarial activities on a chloroquine-resistant Plasmodium falciparum strain, with IC50s ranging from 5 to 10 microM. Structure-activity relationships showed that maximal antimalarial activity occurred in the presence of at least one tetrahydrofuran moiety and a synergistic action with chloroquine was observed. These acetogenins partially inhibited the P.

Development and optimization of polymerase chain reaction-based malaria diagnostic methods and their comparison with quantitative buffy coat assay.

Polymerase chain reaction (PCR)-based assays targeting the small-subunit rRNA were developed and evaluated, allowing for the simultaneous diagnosis of Plasmodium falciparum and Plasmodium vivax DNA in human blood samples. The PCR methods and quantitative buffy coat (QBC) were compared in 402 patients. The heminested PCR method showed a sensitivity of 97.

Antimalarial activity of new gossypol derivatives.

Gossypol, a disesquiterpene extracted from cotton seeds, is known to inhibit strongly the Plasmodium falciparum lactate dehydrogenase, but its high toxicity has stopped any antimalarial drug development. A series of Schiffs bases was synthesized from gossypol by modification of the aldehyde groups responsible for its toxicity. A total of 13 compounds showing low cytotoxicity were then selected and were compared with gossypol for activity against 2 chloroquine-resistant strains of P.

Binding of HIV-1 to RBCs involves the Duffy antigen receptors for chemokines (DARC).

The Duffy Antigen Receptor for Chemokines (DARC) belongs to a family of erythrocyte chemokine receptors that bind C-X-C and C-C chemokines such as interleukin 8 (IL-8), monocyte chemoattractant protein 1 (MCP-1) and regulated-on-activation, normal T cell-expressed and -secreted (RANTES), but not macrophage inflammatory protein 1 alpha (MIP-1 alpha) or MIP-1 beta. DARC has also been identified to a receptor for malaria parasites Plasmodium vivax and Plasmodium knowlesi. In the present study, we show that HIV-1 binds to RBCs from Caucasian individuals via DARC making RBCs able to transmit HIV to peripheral blood mononuclear cells (PBMCs).

Development of a Plasmodium PCR for monitoring efficacy of antimalarial treatment.

We report in this work a highly sensitive and nonradioactive PCR method for the detection of the four species of parasite causing human malaria. Plasmodium-specific primers corresponding to the small-subunit rRNA genes of the malaria parasite were used, and a 291-bp fragment was amplified. Our results showed a high specificity for the four human Plasmodium species, and we were able to detect one parasite in 50 microl of whole blood.

Identification of a family of Rab G-proteins in Plasmodium falciparum and a detailed characterisation of pfrab6.

As a first step towards developing a set of compartment-specific probes for studying protein trafficking in the malaria-infected erythrocyte, we describe here a family of Plasmodium falciparum Rab proteins. We characterise in detail P. falciparum Rab6 (PfRab6) a marker which in other cells is specific for the Golgi/trans Golgi network.

Small GTP-binding proteins in Plasmodium falciparum.

During its erythrocytic life cycle Plasmodium falciparum exchanges compounds with host cells through phagocytosis and exocytosis. In eucaryotic cells, small GTP-binding proteins of the Ras superfamily appear to be involved in different steps of membrane trafficking and in intracellular signals. In this paper, we investigate the Rab4, Rab6 and Ras-related proteins in P falciparum infected red cells.

Molecular characterisation of the ADP/ATP-transporter cDNA from the human malaria parasite Plasmodium falciparum.

We have isolated a cDNA sequence encoding the ADP/ATP transporter in Plasmodium falciparum. The sequence analysis revealed an open reading frame encoding 301 amino acids and showed significant similarities to known eukaryotic translocases such as that of Chlorella (up to 67.2% identity) and the human transporter (61.

An alternative to DNA extraction for the diagnosis of Pneumocystis carinii pneumonia by polymerase chain reaction using a new oligonucleotide probe.

We have used new specific primers and probe in a polymerase chain reaction (PCR) followed by Southern blot assays to detect Pneumocystis carinii in human bronchoalveolar lavage samples obtained from HIV-infected patients with pulmonary symptoms. To facilitate the procedure we developed a filtration technique without DNA extraction yielding a high sensitivity (18/18 positive results). The high specificity of the technique was shown by testing immunosuppressed patients without P.

Plasmodium falciparum: differential sensitivity in vitro to E-64 (cysteine protease inhibitor) and Pepstatin A (aspartyl protease inhibitor).

We investigated the effect of a cysteine proteinase inhibitor (E-64) and an aspartyl proteinase inhibitor (Pepstatin A) on asexual erythrocytic stages of Plasmodium falciparum in culture. These two protease inhibitors showed different patterns of activity. E-64 acted preferentially against trophozoite and schizont stages.