Antenatal Bartter syndrome (aBS) comprises a heterogeneous group of autosomal recessive salt-losing nephropathies. Identification of three genes that code for renal transporters and channels as responsible for aBS has resulted in new insights into renal salt handling, diuretic action and blood-pressure regulation. A gene locus of a fourth variant of aBS called BSND, which in contrast to the other forms is associated with sensorineural deafness (SND) and renal failure, has been mapped to chromosome 1p. We report here the identification by positional cloning, in a region not covered by the human genome sequencing projects, of a new gene, BSND, as the cause of BSND. We examined ten families with BSND and detected seven different mutations in BSND that probably result in loss of function. In accordance with the phenotype, BSND is expressed in the thin limb and the thick ascending limb of the loop of Henle in the kidney and in the dark cells of the inner ear. The gene encodes a hitherto unknown protein with two putative transmembrane alpha-helices and thus might function as a regulator for ion-transport proteins involved in aBS, or else as a new transporter or channel itself.

Juvenile nephronophthisis (NPH), an autosomal recessive cystic kidney disease, is the primary genetic cause of chronic renal failure in children. About two thirds of patients with NPH carry a large homozygous deletion at the gene locus NPH1 on 2q13. We here identify a novel gene. NPHP1, which extends over most of this common deletion. The 4.5-kb transcript encodes a protein with an SH3 domain, which is highly conserved throughout evolution. The 11-kb interval between the 3' end of NPHP1 and an inverted repeat containing the distal deletion breakpoint was found to contain the first exon of a second gene, MALL. In patients with a hemizygous deletion of the NPH1 region, additional point mutations were found in NPHP1 but not in MALL.

Antenatal Bartter syndrome is a variant of inherited renal-tubular disorders associated with hypokalemic alkalosis. This disorder typically presents as a life-threatening condition beginning in utero, with marked fetal polyuria that leads to polyhydramnios and premature delivery. Another hallmark of this variant is a marked hypercalciuria and, as a secondary consequence, the development of nephrocalcinosis and osteopenia. We have analyzed 15 probands belonging to 13 families and have performed SSCP analysis of the coding sequence and the exon-intron boundaries of the NKCC2 gene; and we report 14 novel mutations in patients with antenatal Bartter syndrome, as well as the identification of three isoforms of human NKCC2 that arise from alternative splicing.

ABSTRACT.Objective. To characterize a rare inherited hypokalemic salt-losing tubulopathy with linkage to chromosome 1p31.Methods. We conducted a retrospective analysis of the clinical data for 7 patients in whom cosegregation of the disease with chromosome 1p31 had been demonstrated. In addition, in 1 kindred, prenatal diagnosis in the second child was established, allowing a prospective clinical evaluation.Results. Clinical presentation of the patients was homogeneous and included premature birth attributable to polyhydramnios, severe renal salt loss, normotensive hyperreninemia, hypokalemic alkalosis, and excessive hyperprostaglandin E-uria, which suggested the diagnosis of hyperprostaglandin E syndrome/antenatal Bartter syndrome. However, the response to indomethacin was only poor, accounting for a more severe variant of the disease. The patients invariably developed chronic renal failure. The majority had extreme growth retardation, and motor development was markedly delayed. In addition, all patients turned out to be deaf.Conclusion. The hypokalemic salt-losing tubulopathy with chronic renal failure and sensorineural deafness represents not only genetically but also clinically a disease entity distinct from hyperprostaglandin E syndrome/antenatal Bartter syndrome. A pleiotropic effect of a single gene defect is most likely causative for syndromic hearing loss. Pediatrics 2001;108(1). URL: http:// www.pediatrics.org/cgi/content/full/108/1/e5; tubulopathy, Bartter syndrome, polyhydramnios, renal failure, syndromic deafness, pleiotropic gene.ABBREVIATIONS. HPS/aBS, hyperprostaglandin E syndrome/ antenatal Bartter syndrome; TAL, thick ascending limb of Henle's loop; PGE 2 , prostaglandin E 2 ; NKCC2, furosemide-sensitive Na-K-2Cl cotransporter; ROMK, renal outer-medullary potassium channel; SND, sensorineural deafness; GFR, glomerular filtration rate; BERA, brainstem-evoked response audiometry; PPN, partial parenteral nutrition. I nherited salt-losing tubulopathies with hypokalemic alkalosis involve an overlapping set of renal tubular disorders that can be subdivided into at least 3 phenotypes: 1) classic Bartter syndrome, 2) Gitelman syndrome, and 3) hyperprostaglandin E syndrome/antenatal Bartter syndrome (HPS/aBS). 1,2 Whereas patients with classic Bartter syndrome and Gitelman syndrome typically present in early infancy and childhood or adolescence, manifestation of HPS/aBS occurs in utero and the neonatal course is severe. 3 The first clinical sign is maternal polyhydramnios caused by fetal polyuria, which regularly results in premature birth between 28 and 34 weeks of gestation. 4,5 Postnatally, affected infants present with the typical pattern of impaired tubular reabsorption in the thick ascending limb of Henle's loop (TAL), including salt wasting, isosthenuric or hyposthenuric polyuria, and hypercalciuria with subsequent medullary nephrocalcinosis. 6 -8 Characteristically, endogenous formation of prostaglandin E 2 (PGE 2 ) is stimulated markedly, resulting in additional aggravation of saluretic polyuri...

Familial juvenile nephronophthisis (NPH), an autosomal recessive cystic disease of the kidney, is the most common genetic cause of end-stage renal disease (ESRD) in the first two decades of life. A gene locus for nephronophthisis type 1 (NPH1) has been mapped by linkage analysis to chromosome 2q13. We performed a haplotype analysis in 16 NPH families with at least two affected patients with the typical history, clinical signs and histology of NPH using microsatellite markers of the NPH1 genetic region. By demonstration of a recombinant event marker D2S1893 was identified as a novel centromeric flanking marker to the NPH1 critical genetic region. Absence of linkage to the NPH1 locus in six NPH families confirmed the existence of at least one additional gene locus for NPH. Linkage to the NPH1 locus was demonstrated in 10 families. In 8 of these families a homozygous deletion was identified. These data permit for the first time the study of the development of renal failure in a subset of NPH1 families, which is most likely homogeneous with regard to the responsible gene locus. We present a statistical description of serial serum creatinine measurements in NPH1. Analysis of renal death revealed a median of 13.1 years. Age-dependent quartiles were generated for serum creatinine. In summary, the new marker provides a diagnostic tool to aid in the diagnosis of NPH, while the progression charts offer a standard for an assessment of the rate of progression to ESRD for patients with NPH1 to be used in future therapeutic trials and for a prediction of the individual course of the disease.