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A Recessive Gene for Primary Vesicoureteral Reflux Maps to Chromosome 12p11-q13

Patricia L. Weng^*,, Simone Sanna-Cherchi^*, Terry Hensle, Ellen Shapiro, Alan Werzberger^||, Gianluca Caridi^¶, Claudia Izzi^**, Anita Konka^*, Adam C. Reese^*, Rong Cheng, Samuel Werzberger^*, Richard N. Schlussel, Robert D. Burk, Joseph H. Lee, Roberto Ravazzolo^||||, Francesco Scolari^**, Gian Marco Ghiggeri^¶, Kenneth Glassberg and Ali G. Gharavi^*

^* Department of Medicine, Division of Nephrology, Columbia University College of Physicians and Surgeons, New York, New York; Department of Pediatrics, Division of Pediatric Nephrology, Mount Sinai School of Medicine, New York, New York; Department of Urology, Columbia University College of Physicians and Surgeons, New York, New York; Department of Urology, New York University School of Medicine, New York, New York; ^|| Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York; ^¶ Laboratory on Pathophysiology of Uremia, G. Gaslini Institute, Genoa, Italy; ^** Division of Nephrology, Hospital of Montichiari, Italy, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, Department of Pediatrics/Genetics, Albert Einstein College of Medicine of Yeshiva University, Department of Epidemiology, Columbia University Mailman School of Public Health; ^|||| Laboratory of Molecular Genetics, G. Gaslini Institute, Genoa, Italy

Correspondence: Dr. Ali G. Gharavi, Division of Nephrology, Columbia University, 1150 Street Nicholas Avenue, Russ Berrie Pavilion #302, New York, NY 10032. Phone: 212-851-5556; Fax: 212-851-5520; E-mail: ag2239{at}columbia.edu

Received for publication November 21, 2008. Accepted for publication February 10, 2009.

Primary vesicoureteral reflux (pVUR) is one of the most common causes of pediatric kidney failure. Linkage scans suggest that pVUR is genetically heterogeneous with two loci on chromosomes 1p13 and 2q37 under autosomal dominant inheritance. Absence of pVUR in parents of affected individuals raises the possibility of a recessive contribution to pVUR. We performed a genome-wide linkage scan in 12 large families segregating pVUR, comprising 72 affected individuals. To avoid potential misspecification of the trait locus, we performed a parametric linkage analysis using both dominant and recessive models. Analysis under the dominant model yielded no signals across the entire genome. In contrast, we identified a unique linkage peak under the recessive model on chromosome 12p11-q13 (D12S1048), which we confirmed by fine mapping. This interval achieved a peak heterogeneity LOD score of 3.6 with 60% of families linked. This heterogeneity LOD score improved to 4.5 with exclusion of two high-density pedigrees that failed to link across the entire genome. The linkage signal on chromosome 12p11-q13 originated from pedigrees of varying ethnicity, suggesting that recessive inheritance of a high frequency risk allele occurs in pVUR kindreds from many different populations. In conclusion, this study identifies a major new locus for pVUR and suggests that in addition to genetic heterogeneity, recessive contributions should be considered in all pVUR genome scans.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673