Nature Genetics
14, 152 - 156 (1996)
doi:10.1038/ng1096-152
Genetic heterogeneity of Barter's syndrome revealed by mutations in the K+ channel, ROMKDavid B. Simon1, Fiona E. Karet1, Juan Rodriguez-Soriano2, Jahed H. Hamdan3, Antonio DiPietro4, Howard Trachtman5, Sami A. Sanjad6
& Richard P. Lifton1, 7
1Howard Hughes Medical Institute, Departments of Medicine and Genetics, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA
2Department of Pediatrics, Hospital de Cruces, Baracaldo, Spain E-48903
3Specialty Pediatric Services Division, Dharan Health Center, Room A-406, Box 76, Dharan 31311, Saudi Arabia
4Ospedale A. Cardarelli, 28 Div. Pediatria, Via A. Cardarelli no.9, 80131 Napoli, Italy
5Department of Pediatrics, Albert Einstein College of Medicine, Schneider Children's Hospital, New Hyde Park, New York 11040−1432, USA
6Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
7Correspondence should be addressed to R.P.L. Mutations in the Na−K−2CI cotransporter (NKCC2), a mediator of renal salt reabsorption, cause Barrier's syndrome, featuring salt wasting, hypokalaemic alkalosis, hypercalciuria and low blood pressure. NKCC2 mutations can be excluded in some Bartter's kindreds, prompting examination of regulators of cotransporter activity. One regulator is believed to be ROMK, an ATP−sensitive K+ channel that 'recycles' reabsorbed K+ back to the tubule lumen. Examination of the ROMK gene reveals mutations that co−segregate with the disease and disrupt ROMK function in four Bartter's kindreds. Our findings establish the genetic heterogeneity of Bartter's syndrome, and demonstrate the physiologic role of ROMK in vivo.
REFERENCES
- Lifton, R.P. Molecular genetics of human blood pressure variation. Science 272, 676−680, (1996). | PubMed | ISI | ChemPort |
- Simon, D.B. et al. Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nature Genet. 12, 24−30 (1996). | Article | PubMed | ISI | ChemPort |
- Simon, D.B. et al. Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2CI cotransporter NKCC2. Nature Genet. 13, 183−188 (1996). | Article | PubMed | ISI | ChemPort |
- Wang, W., Sackin, H. & Giebisch, G. Renal potassium channels and their regulation. Annu. Rev. Physiol. 54, 81−96, (1992). | Article | PubMed | ISI | ChemPort |
- Giebisch, G. Renal potassium channels: an overview. Kidney Int. 48, 1004−1009 (1995). | PubMed | ISI | ChemPort |
- Ho, K. et al. Cloning and expression of an inwardly rectifying ATP-regulated potassium channel. Nature 362, 32−38 (1993). | Article |
- Yano, H. et al. Alternative Splicing of human inwardly rectifying K+ channel ROMK1 mRNA. Mol. Phamac. 45, 854−860 (1994). | ChemPort |
- Shuck, M.E. et al. cloning and characterization of multiple forms of the human kidney ROM-K potassium channel. J. Biol. Chem. 269, 24261−24270 (1994). | PubMed | ISI | ChemPort |
- Lee, W.S. & Hebert, S.C. ROMK inwardly rectifying ATP-sensitive K+ cahnnel. I. Expression in rat distal nephron segments. Am. J. Physiol (Renal Fluid Electrol. Physiol.). 268, F1124−31 (1995). | ChemPort |
- Boim, M.A. et al. ROMK inwardly rectifying ATP-sensitive k+ channel. II. Cloning distribution of alternative forms. Am. J. Physiol (Renal Fluid Electrol. Physiol). 268, F1132−F1140 (1995). | ChemPort |
- Hebert, S.C., ATP-regulated, inwardly rectifying potassium channel from kidney (ROMK). Kidney Int 48, 1010−1016 (1995). | PubMed | ISI | ChemPort |
- Lander, E.S. & Botstein, D. Homozygosity maping : away to map human recessive traits with the DNA of inbred children. Science 236, 1567−1570 (1987). | PubMed | ISI | ChemPort |
- Orita, M. et al. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand confromation polymorphisms. Proc. Natl. Acad. Sci. USA 86, 2766−2770. (1989). | PubMed | ChemPort |
- Xu, Z.-C. et al. Phosphorylation of the ATP-sensitive, inwardly rectifying K+ channel, ROMK, by cyclic AMP-dependent protein kinase. J. Biol. Chem. 271, 9313−9319 (1996). | Article | PubMed | ISI | ChemPort |
- Bell, G., Karam, J. & Rutter, W. Polymorphic DNA region adjacent to the 5' end of the human insulin gene. Proc. Natl. Acad Sci. USA 78, 5759−5763 (1981). | PubMed | ChemPort |
- Lathrop, G.M. et al. Strategies for multilocus linkage in humans. Proc. Natl Acad. Sci. USA 81, 3443−3446 (1984). | PubMed | ChemPort |
|
