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

• Published in: Journal of the American Society of Nephrology Vol. 20; no. 7; pp. 1633 - 1640
• Main Authors: WENG, Patricia L, SANNA-CHERCHI, Simone, WERZBERGER, Samuel, SCHLUSSEL, Richard N, BURK, Robert D, LEE, Joseph H, RAVAZZOLO, Roberto, SCOLARI, Francesco, MARCO GHIGGERI, Gian, GLASSBERG, Kenneth, GHARAVI, Ali G, HENSLE, Terry, SHAPIRO, Ellen, WERZBERGER, Alan, CARIDI, Gianluca, IZZI, Claudia, KONKA, Anita, REESE, Adam C, RONG CHENG
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society of Nephrology 01.07.2009
• Subjects: Alleles; Biological and medical sciences; Chromosome Mapping; Chromosomes, Human, Pair 12 - genetics; Clinical Research; Female; Genes, Recessive - genetics; Genetic Linkage - genetics; Humans; Italy; Jews - genetics; Male; Medical sciences; Models, Genetic; Nephrology. Urinary tract diseases; Pedigree; Quantitative Trait Loci - genetics; United States; Urinary system involvement in other diseases. Miscellaneous; Urinary tract. Prostate gland; Vesico-Ureteral Reflux - ethnology; Vesico-Ureteral Reflux - genetics; White People - genetics; United States; Italy; Genetic mapping; Nephrology; Urinary system disease; Vesicoureteral reflux; Primary; Recessive character; Bladder disease; Chromosome C12; Urinary tract disease; Urology; Genetic disease
• ISSN: 1046-6673; 1533-3450; 1533-3450
• DOI: 10.1681/ASN.2008111199

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.