Daniella Magen, MD
Assistant Professor in Pediatrics/Pediatric Nephrology
MD, 1993 - Technion, Israel
Exploring the genetic basis of hereditary renal and metabolic disorders
My research explores 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 identified that a mutation in the kidney-specific sodium-phosphate cotransporter NaPi-IIa results in autosomal recessive renal proximal tubulopathy with hypophosphatemic rickets and renal failure. One of our ongoing projects aims to characterize the molecular mechanism underlying this novel disease-causing mutation. Functional studies in Xenopus laevis oocytes and opossum kidney cells indicate that the mutation results in loss-of-function, as the mutant NaPi-IIa transporter fails to reach the plasma membrane. Preliminary results indicate a potential role for endoplasmic reticulum-associated degradation (ERAD) in the pathophysiology of the trafficking defect of the mutant NaPi-IIa. Notably, a link between the pathogenesis of proximal tubulopathy and ERAD pathways may shed light on novel disease mechanisms underlying more common proximal tubular disorders and their associated renal failure.
Magen D, Ofir A, Berger L, Goldsher D, Eran A, Katib N, Nijem Y, Vlodavsky E, Tzur S, Behar DM, Fellig Y, and Mandel H. 2015. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with a loss-of-function mutation in CDK5. Hum. Genet. 134, 305-314.
Mannstadt M, Magen D, Segawa H, Stanley T, Sharma A, Sasaki S, Bergwitz C, Mounien L, Boepple P, Thorens B, Zelikovic I, and 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. 97, E1978-1986.
Nakhoul F, Nakhoul N, Dorman E, Berger L, Skorecki K, and Magen D. Gitelman’s syndrome: a pathophysiological and clinical update. Endocrine 41, 53-57.
Magen D, 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, pp.727-770.
Magen D, Berger L, Coady MJ, Ilivitzki A, Militianu D, Tieder M, Selig S, Lapointe JY, Zelikovic I, and Skorecki K. 2010. A loss of function mutation in NaPi-IIa and renal Fanconi’s syndrome. N. Engl. J. Med. 362, 1102-1109.
Localization of mutant or wild type NaPi-IIa in transfected opossum kidney cells.
Laser scanning confocal microscopy of opossum kidney cells transfected with wild type (WT) (a-c) or mutant (Mut) (d-f) enhanced green fluorescent protein (EGFP)-tagged NaPi-IIa (green); actin is conjugated with phalloidin Alexa Fluor 660 (red), and nuclei are stained with DAPI (blue). The majority of WT EGFP-tagged NaPi-IIa is localized to the plasma membrane as expected (b) and colocalizes with actin (merged image-c). Mutant NaPi-IIa appears in the cytoplasmic compartment (e), and is not colocalized with actin at the plasma membrane (f).