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Clinical and Genetic Spectrum of Bartter Syndrome Type 3

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Clinical and Genetic Spectrum of Bartter Syndrome Type 3 CLINICAL RESEARCH www.jasn.org Clinical and Genetic Spectrum of Bartter Syndrome Type 3 † †‡ ǁ Elsa Seys,* Olga Andrini, § Mathilde Keck, Lamisse Mansour-Hendili,§ †† ǁ ‡‡ ‡‡ Pierre-Yves Courand,¶** Christophe Simian, Georges Deschenes, §§ Theresa Kwon, §§ ǁǁ Aurélia Bertholet-Thomas, Guillaume Bobrie,¶¶ Jean Sébastien Borde,*** ††† ‡‡‡ ǁǁǁ Guylhène Bourdat-Michel, Stéphane Decramer, Mathilde Cailliez,§§§ Pauline Krug,§§ †††† ‡‡‡‡ Paul Cozette,¶¶¶ Jean Daniel Delbet,**** Laurence Dubourg, Dominique Chaveau, ǁǁǁǁ Marc Fila,§§§§ Noémie Jourde-Chiche, ¶¶¶¶ Bertrand Knebelmann,§§***** ††††† †††† ‡‡‡‡‡ Marie-Pierre Lavocat, Sandrine Lemoine, Djamal Djeddi, Brigitte Llanas,§§§§§ ǁǁǁǁǁ †††††† Ferielle Louillet, Elodie Merieau,¶¶¶¶¶ Maria Mileva,****** Luisa Mota-Vieira, ‡‡‡‡‡‡ ǁǁǁǁǁǁ Christiane Mousson, François Nobili,§§§§§§ Robert Novo, ††††††† Gwenaëlle Roussey-Kesler,¶¶¶¶¶¶ Isabelle Vrillon,******* Stephen B. Walsh, †‡ ‡‡‡‡‡‡‡ ǁ ‡‡‡‡‡‡‡ Jacques Teulon, Anne Blanchard,§**§§ and Rosa Vargas-Poussou §§ Due to the number of contributing authors, the affiliations are listed at the end of this article. ABSTRACT Bartter syndrome type 3 is a clinically heterogeneous hereditary salt-losing tubulopathy caused by mutations of the chloride voltage-gated channel Kb gene (CLCNKB), which encodes the ClC-Kb chlo- ride channel involved in NaCl reabsorption in the renal tubule. To study phenotype/genotype corre- lations, we performed genetic analyses by direct sequencing and multiplex ligation-dependent probe amplification and retrospectively analyzed medical charts for 115 patients with CLCNKB mutations. Functional analyses were performed in Xenopus laevis oocytes for eight missense and two nonsense mutations. We detected 60 mutations, including 27 previously unreported mutations. Among patients, 29.5% had a phenotype of ante/neonatal Bartter syndrome (polyhydramnios or diagnosis in the first month of life), 44.5% had classic Bartter syndrome (diagnosis during childhood, hypercalciuria, and/or polyuria), and 26.0% had Gitelman-like syndrome (fortuitous discovery of hypokalemia with hypomag- nesemia and/or hypocalciuria in childhood or adulthood). Nine of the ten mutations expressed in vitro decreased or abolished chloride conductance. Severe (large deletions, frameshift, nonsense, and es- sential splicing) and missense mutations resulting in poor residual conductance were associated with younger age at diagnosis. Electrolyte supplements and indomethacin were used frequently to induce catch-up growth, with few adverse effects. After a median follow-up of 8 (range, 1–41) years in 77 patients, chronic renal failure was detected in 19 patients (25%): one required hemodialysis and four underwent renal transplant. In summary, we report a genotype/phenotype correlation for Bartter syn- drometype3:completeloss-of-functionmutationsassociated with younger age at diagnosis, and CKD was observed in all phenotypes. J Am Soc Nephrol 28: 2540–2552, 2017. doi: https://doi.org/10.1681/ASN.2016101057 Received October 3, 2016. Accepted February 27, 2017. Correspondence: Dr. Rosa Vargas-Poussou, Hôpital Européen George Pompidou, INSERM, UMR970, Paris-Cardiovascular Research Center, E.S. and O.A. contributed equally to this work. 20-40 rue Leblanc, 75015 Paris, France. Email: [email protected] Published online ahead of print. Publication date available at Copyright © 2017 by the American Society of Nephrology www.jasn.org. 2540 ISSN : 1046-6673/2808-2540 JAmSocNephrol28: 2540–2552, 2017 www.jasn.org CLINICAL RESEARCH Bartter syndromes (BS) and Gitelman syndrome (GS) are au- RESULTS tosomal recessive salt-losing tubulopathies caused by defective salt reabsorption. They are characterized by hypokalemia, met- Population abolic alkalosis, and secondary aldosteronism, with normal or We retrospectively analyzed results for 115 patients (56 men low BP.1,2 BS are classified by phenotype (antenatal or classic) and 59 women) from 111 families with CLCNKB mutations or genotype (types 1–5). Antenatal BS (ABS) is the most severe evaluated at the Genetics Department of Georges Pompidou form, characterized by polyhydramnios, premature birth, life- European Hospital over the last 15 years. A history of consan- threatening episodes of neonatal salt and water loss, hyper- guinity was recorded for 22 families; the geographic origin is calciuria, and early-onset nephrocalcinosis.3 Classic BS (CBS) shown in Supplemental Tables 1–3. occurs in infancy or early childhood and is characterized by marked salt wasting and hypokalemia, leading to polyuria, Initial Clinical Presentation polydipsia, volume contraction, muscle weakness, growth re- Thirty-four patients from 32 families (29.5%) presented with tardation and, sometimes, nephrocalcinosis.4 BS types 1, 2, ABS/NBS, 51 patients from 49 families (44.5%) presented and 3 are caused by mutations of genes expressed in the thick with CBS, and 30 patients from 30 families (26%) presented ascending limb (TAL) of the loop of Henle encoding the lu- with GLS. 2 minal Na+–K+–2Cl cotransporter (SLC12A1; OMIM #601678), the luminal K+ channel ROMK (KCNJ1;OMIM Mutations and Large Rearrangements #241200), and the basolateral chloride channel ClC-Kb Genetic status and mutation type were determined for each (CLCNKB; OMIM #607364), respectively.5–7 Loss-of- initial phenotype group (Table 1). The detailed genotypes of function mutations of BSND encoding barttin, an essential each patient are summarized in Supplemental Tables 1–3. The b subunit for chloride channels, cause BS type 4a with deletion of a single allele was excluded in patients with homo- sensorineural deafness (OMIM #602522).8 Simultaneous zygous point mutations and no consanguinity, and molecular mutations of CLCNKB and CLCNKA cause type 4b BS abnormalities of the other genes implicated in GS and BS were (OMIM #613090).9 Finally, severe gain-of-function muta- excluded in patients with only one heterozygous mutation. tions of the extracellular Ca2+-sensing receptor gene can The breakpoints of large rearrangements were not character- result in a Bartter-like syndrome (BS type 5, OMIM ized; in consequence, we cannot exclude the possibility that #601199).10,11 GS (OMIM #263800) is a milder disease fre- patients with homozygous deletions from nonconsanguine- quently associated with hypomagnesemia and hypocalciuria. ous families harbored two different deletions. Testing was car- GS is often asymptomatic or associated with mild symptoms, ried out for both parents in 22 families and only the mother in such as muscle weakness, salt craving, paresthesia, and tetany. seven families. In all cases, parents were heterozygous for GS is related to loss-of-function mutations of the SLC12A3 the homozygous mutation detected in the proband or for gene encoding the apically expressed thiazide-sensitive NaCl one of the two mutations detected in compound heterozygous cotransporter of the distal convoluted tubule (DCT).12 probands. The first described patients with BS type 3 had a clinical Sixtydifferent mutations were detected: 55% missense, 13% phenotype corresponding to CBS.7 Considerable phenotypic frameshift, 12% nonsense, 10% large deletions, and 10% variability has since been described: CLCNKB mutations can splice-site mutations (Figure 1). Twenty-seven of these muta- also underlie the ABS, neonatal BS (NBS), and Gitelman-like tions were previously unknown (Figure 2, A and B, Supple- (GLS) phenotypes.13–15 This study aimed to shed light on the mental Tables 1–3).Twoofthethreesplice-sitemutations phenotypic heterogeneity of BS type 3 by investigating phe- disrupt the obligatory consensus donor or acceptor splice notype/genotype correlations in a very large French cohort, site and were considered pathogenic as likely to cause and by evaluation of published results and original data for exon skipping and frameshift. The variant at position 26 in vitro expression. intheacceptorsiteofexon14isaknownrarevariant Table 1. Genetic status of patients according to initial phenotype, and percentages of mutated alleles by phenotype and mutation type Genetic Status, No. of Patients (%) Type Of Mutation: No. (%) of Mutated Alleles (N=216) Phenotype Compound Only One Heterozygous Large Splice-Site Frameshift/Nonsense Missense Homozygous Heterozygous Mutation Deletions Mutations Mutation Mutations ABS/NBS 22 (65) 10 (29) 2 (6)a 37 (56) 7 (11) 5 (7) 17 (26) CBS 20 (39) 27 (53) 4 (8)b 37 (38) 6 (6) 22 (22) 33 (34) GLS 14 (47) 8 (27) 8 (27)b 12 (23) 0 10 (19) 30 (58) ALL 56 (49) 45 (39) 14 (12) 86 (40) 13 (6) 37 (17) 80 (37) aMutations in SLC12A1, KCNJ1,andBSND were excluded. bMutations in SLC12A3 were excluded. J Am Soc Nephrol 28: 2540–2552, 2017 Bartter Syndrome Type 3: Clinical and Genetics 2541 CLINICAL RESEARCH www.jasn.org allele as the known mutation p.Pro124Leu in three patients (BR116–1, BR157–1, and GT657–1). Eight of the 13 missense variations affected conserved amino acids and were predicted by at least four out of five tools used for in silico analysis as potentially pathogenic. The remaining five missense changes (p.Ser218Asn, p.Ala254Val, p.Arg395Trp, p.Ile447Thr, and p.Ala469Pro) were classed as variations of unknown signifi- cance (VOUS) (Supplemental Table 4). Among these changes, Figure 1. Type of mutations of CLCNKB detected in patients only the p.Arg395Trp has been described in databases with BS type 3 (n=60). (rs34255952) with an allelic frequency of 2% in blacks and has not been detected in whites. Of the 33 missense mutations detected in our population, 13 were previously shown to result (rs369329893, allele
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