Genetic Cause of Antenatal Bartter Syndrome
Discussion
Two recent studies have shown that mutations in KCNJ1 can induce ABS [5] [6] . The 18 mutations described previously in ABS patients are located in KCNJ1 exon 5. By contrast, we observed a large homozygous deletion in the 5
region of KCNJ1 in patients of a consanguineous family. According to genealogical data and mutation analysis, parents are heterozygous for the deletion. This deletion of at least 884 bp removed all of exons 1 and 2 and intron 1. Exon 3 distant from exon 2 of 15 633 bp was not affected. The cosegregation of the
mutation with the disease and the absence of another alteration in KCNJ1 suggest that this mutation causes ABS in the family reported. Previous cloning of ROMK cDNA [8] [9] [10] has revealed the existence of at least five distinct transcripts in the human kidney ( hROMK1-K5). These transcripts are generated from only one gene by an alternative splicing mechanism and differ by their 5 region. hROMK1 results in the combination of exons 4 and 5. The other four transcripts contain exons 1 and 5 and variable combination of exons 2 and 3. Transcription could be initiated from either the 5 end of exon 1 or exon 4
[10] . The deletion of exon 1 transcription elements observed in patients should lead to the absence of hROMK2-K5 transcripts, whereas hROMK1 transcripts should be present. Therefore, neither the hROMK2 nor the hROMK3 peptide encoded by the hROMK2- K5 transcripts should be present in these patients, while the hROMK1 isoform would normally be translated from the hROMK1 transcript [9] .
The most convincing hypothesis to explain expression of ABS in the family reported is that only hROMK2-K5 transcripts are expressed in medullary thick ascending limb of Henle, whereas hROMK1 transcripts are located in another part of the nephron. This hypothesis is supported by a previous report on rat ROMK transcripts. Indeed, rROMK are expressed in different parts of the nephron [11] . However, we cannot exclude fetal and postnatal regulation of hROMK expression. Indeed, regulation of ROMK during gestation has been observed in the pregnant rat uterus [12] . A low level of hROMK1 expression at an early stage of life would be insufficient to balance the lack of hROMK2-3 expression. This could explain the improvement in the disease with age. Another hypothesis is that all hROMK isoforms are necessary to form a functional K channel. This is supported by immunoblot analysis performed on the rat kidney nephron, which revealed high molecular weight proteins in addition to proteins of the expected size [13] .
Acknowledgments
This work was supported in part by the EU Commission BIOMED 2 (BMHY-CTGB-0260). We are extremely grateful to all members of the family who participated in this work. We also thank the International Collaborative Study Group for Bartter-Like Syndromes for their contributions to this project; C. Magnier, C. Chauve, and V. Gaston for excellent technical assistance; and D. Raine for editing the English.
Journal of the American Society of Nephrology
Volume 9 Number 12 December 1998
Copyright 1998 American Society of Nephrology
Correspondence to Dr. Delphine Feldmann, Laboratory of Biochemistry, Armand Trousseau Hospital, 24 Rue du Dr. A Netter, 75012 Paris, France.
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