Title: Localization of a Novel Glomerulocystic Kidney Disease (GCKD) Locus to Chromosome 11
Wensheng Pan, PhD 1*, Julianne S. Collins, PhD 2, Bekir Tanriover, MD 1 and Lisa M. Guay-Woodford, MD 1. 1Medicine and Pediatrics, University of Alabama at Birmingham, Birmingham, AL and 2Greenwood Genetic Center, Greenwood, SC.
Background: GCKD is a heterogeneous disorder that can occur in association with maturity onset diabetes of the young (MODY) due to mutations in HNF1beta, in infants with autosomal dominant polycystic kidney disease, or in the context of either malformation syndromes or urinary tract obstruction. We have previously characterized a large, three-generation African-American (AA) family with dominantly-inherited GCKD and excluded linkage with PKD1, PKD2, and the human orthologue of mouse jcpk (Sharp et al. JASN 1997). Disease expression in this family is confined to the kidney. The renal phenotype is quite variable, ranging from sonographic abnormalities with or without hypertension to end-stage renal disease.
Methods: We performed a whole-genome scan using the Affymetrix GeneChip Hu-SNPTM Mapping Assay on 8 GCKD affected individuals, 2 obligate carriers, and 4 phenotypically unaffected family members. Of the 1494 single nucleotide polymorphism (SNP) markers on this chip, 1163 were assigned to chromosome (chr) localizations using physical mapping information. Our scan was conducted at an average interval of 4-cM with an average largest gap per chr of 22.5-cM. AA SNP allele frequencies, which are not publically available, were calculated based on analyses in 29 unrelated AA individuals.
Results: Pairwise and multipoint analyses using the FASTLINK program identified a putative candidate interval on chr 11p15. Further typing in these 14 individuals as well as 6 additional, phenotypically unaffected family members was performed with six microsatellite markers spaced at 2-cM intervals across the candidate interval. The highest 2-point logarithm of odds (LOD) score of 2.7 was obtained for marker D11S1338 and multipoint analyses yielded a maximum LOD score of 3.0. Haplotype analyses refined the candidate region to an 11.1-cM interval between D11S922 and D11S909.
Conclusion: This is the first reported localization of a renal disease gene using a SNP-based genome scan. With this new technique and microsatellite-based fine-mapping, we have localized a novel GCKD locus to an 11-cM interval on chr 11p15.