A G-->A transition creates a branch point sequence and activation of a cryptic exon, resulting in the hereditary disorder neurofibromatosis 2

We describe a G-->A transition within intron 5 of the NF2 gene. This mutation creates a consensus splice branch point sequence. To our knowledge this is the first report of a mutation that creates a functional branch point sequence in a human hereditary disorder. The new branch point sequence is located 18 bp upstream of a consensus splice acceptor site. A consensus splice donor site is found 106 bp 3' of the acceptor site. Asa consequence the G-->A transition results in an alternatively spliced mRNA containing an additional exon 5a of 106 bp derived from intron sequences. We cloned the mutant cDNA and show that due to an in-frame stop codon the cDNA codes for a truncated NF2 protein. The mutation was observed in three affected members of an NF2 family. In a tumour of one of the family members both alternatively spliced and wild-type mRNA were found, although the wild-type allele of the gene is absent due to an interstitial deletion on chromosome 22. We also show that immunoprecipitations reveal the presence of full-length wild-type NF2 protein in the tumour lysate. These data support the hypothesis that some degree of normal splicing of the mutant precursor RNA is taking place. It is therefore likely that this residual activity of the mutant allele explains the relatively mild phenotype in the family. These data also indicate that complete inactivation of the gene is not required for tumour formation.      

Immunological Studies of Patients with Down's Syndrome

Abstract. Recurrent diarrhoea and weight loss in many adult patients with Down's syndrome (DS), initiated a search for malabsorption based on determination of serum IgG and IgA antibody levels to dietary antigens. The results were compared with measurements of autoantibodies and serum zinc levels. DS patients had increased IgG and IgA activities to gluten proteins, casein and ovalbumin compared with an age- and sex-matched group of other mentally retarded patients in the same institution. Intestinal biopsy was performed in six of the 38 patients; one had total and one partial villous atrophy. Serum zinc was significantly lower in DS patients (median 14.7 μmol/l, range 5.5–20 μmol/l) than in the controls (median 16.4 μmol/l, range 12.7–19.5 μmol/l). DS patients with increased IgA activity to gluten weighed less and had lower concentrations of zinc in serum than DS patients with normal IgA activity. Twenty-eight per cent of the DS patients had autoantibodies to the thyroid gland. Our results suggest intestinal malfunction in DS, perhaps related to a defect of immune regulation caused by reduced levels of zinc in serum.     

Renal thorium deposition associated with transitional cell carcinoma: radiologic demonstration in two patients

Abdominal radiography, excretory urography, retrograde pyelography, and computed tomography were performed in two patients who had undergone retrograde pyelography with thorium dioxide (Thorotrast) approximately 40 years ago. Both patients developed a transitional cell carcinoma due to suburothelial thorium deposition. Typical thorium densities were demonstrated at CT in the peripelvicalyceal area as well as in retroperitoneal lymph nodes. Elderly patients in whom radiographic examination reveals retained Thorotrast in the kidney should be followed up because of the high risk of renal carcinoma.     

Atrap Deficiency Increases Arterial Blood Pressure and Plasma Volume

The angiotensin receptor-associated protein (Atrap) interacts with angiotensin II (AngII) type 1 (AT1) receptors and facilitates their internalization in vitro, but little is known about the function of Atrap in vivo. Here, we detected Atrap expression in several organs of wild-type mice; the highest expression was in the kidney where it localized to the proximal tubule, particularly the brush border. There was no Atrap expression in the renal vasculature or juxtaglomerular cells. We generated Atrap-deficient (Atrap−/−) mice, which were viable and seemed grossly normal. Mean systolic BP was significantly higher in Atrap−/− mice compared with wild-type mice. Dose-response relationships of arterial BP after acute AngII infusion were similar in both genotypes. Plasma volume was significantly higher and plasma renin concentration was markedly lower in Atrap−/− mice compared with wild-type mice. ¹²⁵I-AngII binding showed enhanced surface expression of AT1 receptors in the renal cortex of Atrap−/− mice, accompanied by increased carboanhydrase-sensitive proximal tubular function. In summary, Atrap−/− mice have increased arterial pressure and plasma volume. Atrap seems to modulate volume status by acting as a negative regulator of AT1 receptors in the renal tubules.Angiotensin II (AngII) is the primary end point of the renin-angiotensin (RAS) cascade. AngII exerts multiple functions, including mediation of vasoconstriction, stimulation of aldosterone release, and promotion of renal salt/water reabsorption. These classical effects of AngII, which eventually all result in a rise of arterial blood pressure (BP), are thought to be primarily mediated by AngII type 1 (AT1) receptors. Because changes in the activity of the systemic RAS cascade similarly affect all different accessible target tissues, it is reasonable to assume that strategies that allow for local and temporal modification of the sensitivity of AT1 receptors have evolved. In this context, modulation of AT1 receptor expression, receptor desensitization, and internalization all have been described to modify locally the AT1-related effects of AngII.^1–8 In addition, a growing number of proteins seem to bind to the AT1 receptor and either enhance or suppress AT1 receptor function.^9–13Of the known proteins that can interact with AT1 receptors, the function of the angiotensin receptor–associated protein (Atrap) is the best characterized.^10,14 Atrap is a 19-kD protein with three potential transmembrane domains, and it binds to the C-terminal intracellular portion of the AT1 receptor.¹⁵ Atrap catalyzes the internalization of the AT1 receptor in cultured vascular smooth muscle cells.^14,16 Also, Atrap inhibits AngII-mediated intracellular signaling in vitro.¹⁷ Overall, the data suggest an inhibitory effect of Atrap on AT1 receptor function in vitro.Regarding the in vivo function of Atrap, a recently generated transgenic mouse line with overexpression of Atrap in the heart, aorta, and femoral artery showed reduced inflammatory vascular remodeling and reduced heart hypertrophy as compared with transgene-negative controls.¹⁸ The authors concluded that Atrap attenuates AT1-mediated signaling under pathophysiologic conditions.¹⁸To assess the in vivo function of Atrap, we generated Atrap-deficient (Atrap−/−) mice. Vascular responsiveness to AngII was virtually unaltered in Atrap−/− mice compared with wild-type mice; however, loss of Atrap resulted in increased plasma volume and elevated arterial BP. Renal cortical AngII binding and acetazolamide-sensitive tubular function were enhanced in Atrap−/− mice compared with wild-type controls. We propose that Atrap is a negative modulator of renal AngII signaling and that loss of Atrap results in enhanced renal reabsorptive function, leading to volume expansion and hypertension.     

Sequelae of acute renal infections: CT evaluation

Seventeen patients with upper urinary tract infection who underwent 51 computed tomographic studies (two to five per patient; mean, three) were retrospectively evaluated. Five to 10 days after the initial examination, there was little change in parenchymal abnormalities, but perirenal inflammation worsened and then subsided over 2-8 weeks. Enlargement of the affected kidney, present initially in 12 patients, persisted up to 6 weeks and resolved by 10-16 weeks. Abnormalities of parenchymal contrast material enhancement persisted for 1-2 months. New cortical scars appeared in six of 12 patients with an initially normal renal contour and in one of five patients who had scars initially. Three patients with a renal abscess developed a new calyceal diverticulum, presumably by rupture of the abscess into the collecting system. The present study shows that abnormalities of renal size and enhancement persist for weeks to months after clinical signs of infection resolve and that scarring in adults with urinary tract infection occurs more frequently than was previously realized.