The gene -- KCNJ10 -- encodes a potassium channel expressed in the brain, inner ear, and kidney, Robert Kleta M.D., Ph.D., of University College London, and colleagues reported in the May 7 issue of the New England Journal of Medicine.
The finding comes from an investigation of five children in two consanguineous families who had had epilepsy from birth, but also had ataxia, sensorineural deafness, and renal salt-losing tubulopathy with normotensive hypokalemic metabolic alkalosis.
The researchers dubbed the constellation of symptoms the EAST syndrome, for epilepsy, ataxia, sensorineural deafness, and tubulopathy.
To pin down its cause, Dr. Kleta and colleagues performed a whole-genome linkage analysis and zeroed in on a region on chromosome one that includes about 800,000 base-pairs.
The region had a lod score of 4.98. The lod score is a statistical estimate of whether loci are likely to be inherited together as a package; a lod score of 3.0 means the odds are a thousand to one in favor of genetic linkage.
This region contained 31 known genes, including KCNJ10, which was attractive because mice with the gene deleted have seizures, ataxia, and sensorineural deafness, although their kidney function had not been studied, the researchers said.
Sequencing of the region revealed a missense mutation -- leading to loss of function -- in both copies of the gene in the four affected children in one family.
A different missense mutation -- again in both copies of the gene -- was found in the affected member of the other family, the researchers said.
In each family, the parents carried an unimpaired copy of the gene. Sequencing of ethnically matched controls (162 alleles for the first family and 108 for the second) did not find either mutation.
In cells where it is normally expressed, the loss of function of KCNJ10 interferes with a basic cellular process, in which the sodium-potassium pump Na+/K+-ATPase generates a concentration gradient for potassium movement through a potassium channel.
In normal cells, this results in a potassium current that drives a variety of cell functions, but those functions are inhibited when the potassium channel, KCNJ10, is impaired.
The EAST syndrome "should be suspected in patients presenting with any cardinal signs or symptoms of epilepsy, ataxia, or sensorineural deafness, especially if a concurrent electrolyte disorder, such as hypokalemia or hypomagnesemia, is diagnosed," the researchers argued.
"At least two clinically relevant lessons may be derived from the study," according to Markus Bleich, M.D., of Physiologisches Institut der Christian-Albrechts-UniversitÃ¤t zu Kiel in Kiel, Germany.
The first, he wrote in an accompanying editorial, is that "connections have yet to be made" between thousands of genes and many physiological functions and diseases.
The second lesson, Dr. Bleich said, is that it may be rewarding to look at organs other than the one that appears to have the primary condition. In this case, the findings link the kidney, brain and inner ear, he said.
|The study was supported by the National Human Genome Research Institute, the NIH, the Great Ormond Street Hospital, St. Peter's Trust for Kidney, Bladder, and Prostate Research, the Grocers' Charity, the David and Elaine Potter Charitable Foundation, and Deutsche Forschungsgemeinschaft. Dr. Kleta reported no conflicts.
Zalman S. Agus, MD Emeritus Professor
University of Pennsylvania School of Medicine
New England Journal of MedicineSource Reference: Bockenhauer D, et al "Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations" N Engl J Med 2009; 360: 1960-70.
New England Journal of MedicineSource Reference: Bleich M "Membrane physiology -- bridging the gap between medical disciplines" N Engl J Med 2009; 360: 2012-14.