Daniella Magen, MD
Assistant Professor of Pediatrics/Pediatric Nephrology
MD, 1993 - Technion, Israel
Exploring the genetic basis of hereditary renal and metabolic disorders
My research focus is to delineate the genetic basis of hereditary renal and metabolic disorders in consanguineous families from Northern Israel by combining the powerful techniques of homozygosity mapping with whole exome capture and next generation sequencing. Recently we found that a novel disease-causing mutation in the kidney-specific sodium-phosphate cotransporter Na/Pi-IIa underlies autosomal recessive renal proximal tubulopathy associated with hypophosphatemic rickets and renal failure. Functional studies in Xenopus laevis oocytes and in opossum kidney cells indicate that this mutation causes a loss of Na/Pi-IIa function, resulting from failure of the transporter to reach the plasma membrane. Preliminary results indicate a potential role for endoplasmic reticulum-associated degradation (ERAD) in the trafficking defect of the mutant Na+/Pi-IIa. Our research linking the pathogenesis of proximal tubulopathy to ERAD pathways may shed light on novel disease mechanisms underlying more common proximal tubular disorders and associated renal failure.
Localization of mutant or wild type NaPi-IIa in transfected opossum kidney cells. Laser scanning confocal microscopy of opossum kidney cells transfected with (a-c) wild type (WT) or (d-f) mutant (Mut) enhanced green fluorescent protein (EGFP)-tagged NaPi-IIa (green). Actin was conjugated with phalloidin Alexa Fluor 660 (red) and nuclei stained with DAPI (blue). Note that the majority of WT EGFP-tagged NaPi-IIa is localized to the plasma membrane as expected (b) and co-localizes with actin (merged image-c). In contrast, mutant NaPi IIa appears in the cytoplasmic compartment (e), and is not co-localized with actin at the plasma membrane (f).
Mannstadt M, Magen D, Segawa H, Stanley T, Sharma A, Sasaki S, Bergwitz C, Mounien L, Boepple P, Thorens B, Zelikovic I, Juppner H. 2012. Fanconi-Bickel Syndrome and Autosomal Recessive Proximal Tubulopathy with Hypercalciuria (ARPTH) are Allelic Variants Caused by GLUT2 Mutations. J Clin Endocrin Metab. 10, 2012-1279.
Magen D and Zelikovic I. 2011. Hereditary Tubular Disorders of Mineral Handling. In: Pediatric Bone, 2nd edition, Editors: Francis Glorieux, John Pettifor, Harald Jueppner. Elsevier, San Diego, California, 727-770.
Magen D, Berger L, Coady MJ, Ilivitzki A, Militianu D, Tieder M, Selig S, Lapointe JY, Zelikovic I, Skorecki K. 2010. A loss of function mutation in NaPi-IIa and renal Fanconi ’s syndrome. N Engl J Med 362, 1102-1109.