Copyright © 2000 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 67, Issue 3, 647-651, 1 September 2000
doi:10.1086/303051
A Locus for an Autosomal Dominant Form of Progressive Renal Failure and Hypertension at Chromosome 1q21
Daniel H. Cohn1, 2, Tamy Shohat3, Michal Yahav4, Tsafra Ilan5, Gidi Rechavi5, Lily King1 and Mordechai Shohat4, 
, 
1 Ahmanson Department of Pediatrics, Cedars-Sinai Research Institute, Los Angeles
2 Departments of Human Genetics and Pediatrics, UCLA School of Medicine, Los Angeles
3 Israel Center for Disease Control, Israel Ministry of Health, Sheba Medical Center, Tel Hashomer
4 Department of Medical Genetics, Rabin Medical Center and FMRC, Petah Tikva, Israel
5 Department of Pediatric Hematology and Oncology, Sheba Medical Center, Tel Hashomer, and Sackler School of Medicine, Tel Aviv University, Tel Aviv
Address for correspondence and reprints: Dr. Mordechai Shohat, Director, Department of Medical Genetics, Rabin Medical Center, Beilinson Campus, Petah Tikva 49100, IsraelAbstract
Linkage studies were performed in a large family with an autosomal dominant phenotype characterized by nephropathy and hypertension. In this family of Iraqi Jewish origin, the nephropathy develops into progressive renal failure. By performing a genomewide linkage search, we localized the disease gene to chromosome 1q21; the highest LOD score was obtained for the marker at locus D1S305, which yielded a maximum LOD score of 4.71 at a recombination fraction of 0. Recombination mapping defined an interval of ∼11.6 cM, between the markers at loci D1S2696 and D1S2635, that contains the disease gene. Localization of the disease-causing gene in this family represents a necessary step toward isolation of the defective gene and toward a deeper understanding of the mechanisms of hypertension and progressive renal failure.
Article Information
PubMed
Related Articles
- African American Hypertensive Nephropathy Maps to a New Locu...African American Hypertensive Nephropathy Maps to a New Locus on Chromosome 9q31-q32
The American Journal of Human Genetics, Volume 73, Issue 2, 1 August 2003, Pages 420-429
Ki Wha Chung, Robert E. Ferrell, Demetrius Ellis, Michael Barmada, Michael Moritz, David N. Finegold, Ronald Jaffe and Abhay Vats
AbstractHypertensive nephropathy (HN) and focal segmental glomerulosclerosis (FSGS) are significant causes of end-stage renal disease (ESRD), but no genes or loci have been associated with this phenotype among African Americans, a group at high risk. We performed a genomewide linkage scan with ∼400 microsatellite markers on 23 individuals of a large four-generation African American family with 18 affected individuals (7 with ESRD), in which the 13-year-old proband (also with ESRD) presented with hypertension and proteinuria (2–4 g/day) and underwent a kidney biopsy that revealed FSGS-like lesions with arteriolar thickening. A genomewide scan revealed LOD scores of >2.5 for markers on chromosomes 3 and 9, and fine mapping was performed on 5 additional members (total 28 members) that showed a maximum multipoint LOD score of 5.4 in the 9q31-q32 region, under an autosomal dominant model with 99% penetrance. This 8-cM (6-Mb) region is flanked by markers D9S172 and D9S105, and further candidate gene sequencing studies excluded the coding regions of three genes (ACTL7A, ACTL7B, and CTNNAL1). To our knowledge, this is the first report of a locus, denoted as “HNP1,” for the HN/FSGS phenotype in a large African American family with dominantly inherited nephropathy characterized by ESRD, hypertension, and some features of FSGS.
Abstract | | - Familial Juvenile Hyperuricemic Nephropathy: Localization of...Familial Juvenile Hyperuricemic Nephropathy: Localization of the Gene on Chromosome 16p11.2—and Evidence for Genetic Heterogeneity
The American Journal of Human Genetics, Volume 66, Issue 6, 1 June 2000, Pages 1989-1994
Blanka Stibůrková, Jacek Majewski, Ivan Šebesta, Wenyong Zhang, Jurg Ott and Stanislav Kmoch
AbstractFamilial juvenile hyperuricemic nephropathy (FJHN), is an autosomal dominant renal disease characterized by juvenile onset of hyperuricemia, gouty arthritis, and progressive renal failure at an early age. Using a genomewide linkage analysis in three Czech affected families, we have identified, on chromosome 16p11.2, a locus for FJHN and have found evidence for genetic heterogeneity and reduced penetrance of the disease. The maximum two-point LOD score calculated with allowance for heterogeneity (HLOD) was 4.70, obtained at recombination fraction 0, with marker D16S3036; multipoint linkage analysis yielded a maximum HLOD score of 4.76 at the same location. Haplotype analysis defined a 10-cM candidate region between flanking markers D16S501 and D16S3113, exhibiting crossover events with the disease locus. The candidate interval contains several genes expressed in the kidney, two of which—uromodulin and NADP-regulated thyroid-hormone–binding protein—represent promising candidates for further analysis.
Abstract | | - Reconstruction of a Functional Human Gene Network, with an A...Reconstruction of a Functional Human Gene Network, with an Application for Prioritizing Positional Candidate Genes
The American Journal of Human Genetics, Volume 78, Issue 6, 1 June 2006, Pages 1011-1025
Lude Franke, Harm van Bakel, Like Fokkens, Edwin D. de Jong, Michael Egmont-Petersen and Cisca Wijmenga
AbstractMost common genetic disorders have a complex inheritance and may result from variants in many genes, each contributing only weak effects to the disease. Pinpointing these disease genes within the myriad of susceptibility loci identified in linkage studies is difficult because these loci may contain hundreds of genes. However, in any disorder, most of the disease genes will be involved in only a few different molecular pathways. If we know something about the relationships between the genes, we can assess whether some genes (which may reside in different loci) functionally interact with each other, indicating a joint basis for the disease etiology. There are various repositories of information on pathway relationships. To consolidate this information, we developed a functional human gene network that integrates information on genes and the functional relationships between genes, based on data from the Kyoto Encyclopedia of Genes and Genomes, the Biomolecular Interaction Network Database, Reactome, the Human Protein Reference Database, the Gene Ontology database, predicted protein-protein interactions, human yeast two-hybrid interactions, and microarray coexpressions. We applied this network to interrelate positional candidate genes from different disease loci and then tested 96 heritable disorders for which the Online Mendelian Inheritance in Man database reported at least three disease genes. Artificial susceptibility loci, each containing 100 genes, were constructed around each disease gene, and we used the network to rank these genes on the basis of their functional interactions. By following up the top five genes per artificial locus, we were able to detect at least one known disease gene in 54% of the loci studied, representing a 2.8-fold increase over random selection. This suggests that our method can significantly reduce the cost and effort of pinpointing true disease genes in analyses of disorders for which numerous loci have been reported but for which most of the genes are unknown.
Abstract | | - …more
