2007 JASN IMPACT FACTOR 7.111	HOME   AUTHOR INFO   EDITORIAL BOARD   SUBSCRIBE   FEEDBACK   ALERTS   HELP
advanced	CURRENT ISSUE	ARCHIVES	JASN Express	ONLINE SUBMISSION

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by REYNOLDS, D. M. Articles by SOMLO, S. Search for Related Content PubMed PubMed Citation Articles by REYNOLDS, D. M. Articles by SOMLO, S.

Aberrant Splicing in the PKD2 Gene as a Cause of Polycystic Kidney Disease

DAVID M. REYNOLDS^*, TOMOHITO HAYASHI^*, YIQIANG CAI^*, BARBERA VELDHUISEN, TERRY J. WATNICK, XOSE M. LENS^§, TOSHIO MOCHIZUKI^*, FENG QIAN, YOSHIKO MAEDA^*, LI LI^*, RAGNHEIDUR FOSSDAL^||, ELIECER COTO^¶, GUANQING WU^*, MARTIJN H. BREUNING, GREGORY G. GERMINO, DORIEN J. M. PETERS and STEFAN SOMLO^*

^* Departments of Medicine and Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York
Department of Human Genetics, Sylvius Laboratory, Leiden University, Leiden, Netherlands
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
^§ Complexo Hospitalario, Universitario de Santiago, Santiago de Compostela, Spain
^|| Department of Medical Genetics, National University Hospital, Reykjavik, Iceland
^¶ Servicio de Immunologia, Hospital Central de Asturias, Oviedo, Spain.

Correspondence to Dr. Stefan Somlo, Section of Nephrology, Yale University School of Medicine, LMP 2073, 333 Cedar Street, New Haven, CT 06520-8029. Phone: 203-785-7595; Fax: 203-624-8213; E-mail: stefan.somlo{at}yale.edu

Abstract. It is estimated that approximately 15% of families with autosomal dominant polycystic kidney disease (ADPKD) have mutations in PKD2. Identification of these mutations is central to identifying functionally important regions of gene and to understanding the mechanisms underlying the pathogenesis of the disorder. The current study describes mutations in six type 2 ADPKD families. Two single base substitution mutations discovered in the ORF in exon 14 constitute the most COOH-terminal pathogenic variants described to date. One of these mutations is a nonsense change and the other encodes an apparent missense variant. Reverse transcription-PCR from patient lymphoblast RNA showed that, in addition, both mutations resulted in out-of-frame splice variants by activating cryptic splice sites via different mechanisms. The apparent missense variant produced such a strong splicing signal that the processed transcript from the mutant chromosome did not contain any of the normally spliced, missense product. A third mutation, a nonconservative missense change effecting a negatively charged residue in the third transmembrane span, is likely pathogenic and defines a highly conserved residue consistent with a potential channel subunit function for polycystin-2. The remaining three mutations included two frame shifts resulting from deletion of one or two bases in exons 6 and 10, respectively, and a nonsense mutation due to a single base substitution in exon 4. The study also defined a novel intragenic polymorphism in exon 1 that will be useful in analyzing "second hits" in PKD2. Finally, the study demonstrates that there are reduced levels of normal polycystin-2 protein in lymphoblast lines from PKD2-affected individuals and that truncated mutant polycystin-2 cannot be detected in patient lymphoblasts, suggesting that the latter may be unstable in at least some tissues. The mutations described will serve as critical reagents for future functional studies in PKD2.

This article has been cited by other articles:

				A. Celic, E. T. Petri, B. Demeler, B. E. Ehrlich, and T. J. Boggon Domain Mapping of the Polycystin-2 C-terminal Tail Using de Novo Molecular Modeling and Biophysical Analysis J. Biol. Chem., October 17, 2008; 283(42): 28305 - 28312. [Abstract] [Full Text] [PDF]

				J. Du, M. Ding, S. Sours-Brothers, S. Graham, and R. Ma Mediation of angiotensin II-induced Ca2+ signaling by polycystin 2 in glomerular mesangial cells Am J Physiol Renal Physiol, April 1, 2008; 294(4): F909 - F918. [Abstract] [Full Text] [PDF]

				L. Geng, D. Okuhara, Z. Yu, X. Tian, Y. Cai, S. Shibazaki, and S. Somlo Polycystin-2 traffics to cilia independently of polycystin-1 by using an N-terminal RVxP motif J. Cell Sci., April 1, 2006; 119(7): 1383 - 1395. [Abstract] [Full Text] [PDF]

				D. H. Grimm, A. Karihaloo, Y. Cai, S. Somlo, L. G. Cantley, and M. J. Caplan Polycystin-2 Regulates Proliferation and Branching Morphogenesis in Kidney Epithelial Cells J. Biol. Chem., January 6, 2006; 281(1): 137 - 144. [Abstract] [Full Text] [PDF]

				K. Hackmann, A. Markoff, F. Qian, N. Bogdanova, G. G. Germino, P. Pennekamp, B. Dworniczak, J. Horst, and V. Gerke A splice form of polycystin-2, lacking exon 7, does not interact with polycystin-1 Hum. Mol. Genet., November 1, 2005; 14(21): 3249 - 3262. [Abstract] [Full Text] [PDF]

				R. Ma, W.-P. Li, D. Rundle, J. Kong, H. I. Akbarali, and L. Tsiokas PKD2 Functions as an Epidermal Growth Factor-Activated Plasma Membrane Channel Mol. Cell. Biol., September 15, 2005; 25(18): 8285 - 8298. [Abstract] [Full Text] [PDF]

				V. Babich, W.-Z. Zeng, B.-I. Yeh, O. Ibraghimov-Beskrovnaya, Y. Cai, S. Somlo, and C.-L. Huang The N-terminal Extracellular Domain Is Required for Polycystin-1-dependent Channel Activity J. Biol. Chem., June 11, 2004; 279(24): 25582 - 25589. [Abstract] [Full Text] [PDF]

				Y. Cai, G. Anyatonwu, D. Okuhara, K.-B. Lee, Z. Yu, T. Onoe, C.-L. Mei, Q. Qian, L. Geng, R. Wiztgall, et al. Calcium Dependence of Polycystin-2 Channel Activity Is Modulated by Phosphorylation at Ser812 J. Biol. Chem., May 7, 2004; 279(19): 19987 - 19995. [Abstract] [Full Text] [PDF]

				J. Stekrova, J. Reiterova, M. Merta, J. Damborsky, J. Zidovska, V. Kebrdlova, and M. Kohoutova PKD2 mutations in a Czech population with autosomal dominant polycystic kidney disease Nephrol. Dial. Transplant., May 1, 2004; 19(5): 1116 - 1122. [Abstract] [Full Text] [PDF]

				R. Magistroni, N. He, K. Wang, R. Andrew, A. Johnson, P. Gabow, E. Dicks, P. Parfrey, R. Torra, J. L. San-Millan, et al. Genotype-Renal Function Correlation in Type 2 Autosomal Dominant Polycystic Kidney Disease J. Am. Soc. Nephrol., May 1, 2003; 14(5): 1164 - 1174. [Abstract] [Full Text] [PDF]

				A. KUMANOVICS, G. LEVIN, and P. BLOUNT Family ties of gated pores: evolution of the sensor module FASEB J, October 1, 2002; 16(12): 1623 - 1629. [Abstract] [Full Text] [PDF]

				P. Igarashi and S. Somlo Genetics and Pathogenesis of Polycystic Kidney Disease J. Am. Soc. Nephrol., September 1, 2002; 13(9): 2384 - 2398. [Full Text] [PDF]

				B. PHAKDEEKITCHAROEN, T. J. WATNICK, and G. G. GERMINO Mutation Analysis of the Entire Replicated Portion of PKD1 Using Genomic DNA Samples J. Am. Soc. Nephrol., May 1, 2001; 12(5): 955 - 963. [Abstract] [Full Text]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673