A common NKCC2 mutation in Costa Rican Bartter's syndrome patients

Abstract

Bartter's syndrome involves an overlapping set of closely related renal tubular disorders that can be subdivided into at least three clinical phenotypes: (1) the hypercalciuric antenatal Bartter variant; (2) the classic Bartter variant; and (3) the hypocalciuric-hypomagnesemic Gitelman variant. Recent data demonstrate that in several phenotypically indistinguishable cohorts, antenatal Bartter's syndrome is genetically heterogeneous. In these patients, mutations in the genes encoding either the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) or the ATP-regulated potassium channel ROMK (KCNJI) have been identified. A cohort of 20 Costa Rican patients with a congenital syndrome that bears strong similarities to antenatal Bartter's syndrome but also has several distinct features has recently been described. In this cohort, we have identified a predominant mutation that introduces a premature stop in codon W625 of the NKCC2 gene (SCL12A1). This mutant allele is contained on a single common haplotype, suggesting that the majority of antenatal Bartter's syndrome patients in Costa Rica share a single common ancestor.

Historical and geographical distribution of the founder mutation c.610G>A; p.Ala204Thr in the CLCNKB gene linked to Bartter syndrome type III in Spain

“…This fact, along with finding several heterozygous carriers (for p. Ala204Thr) in individuals with ancestry originated from Mestanza (a town founded in the 11th century, localized at the South of Ciudad Real) and a dot of confluence of Cañada Real Segoviana (4) and Cañada Real Soriana Oriental (5) ( Figure 2 ), seemed to support our hypothesis. Our data are also consistent with studies establishing a strong association between specific-unique mutations and population founder effects on BS [ 7–9 ], such as in Korea and Japan [ 8 , 9 ] or Costa Rican populations [ 10 ] ( Supplementary data, Table S2 ).…”

A long‐term study of the effects of SLC12A1 homozygous mutation (g.62382825G>A, p.Pro372Leu) in Japanese Black cattle

“…The homozygous loss‐of‐function SLC12A1 mutation in humans is responsible for the antenatal form of Bartter syndrome type I (Kurtz et al., 1997; Nozu et al., 2009; Simon et al., 1996; Vargas‐Poussou et al., 1998). This is an autosomal recessive disorder characterized by abnormally high levels of amniotic fluid surrounding the affected fetus (polyhydramnios) that closely resembles the symptoms of hydrallantois in Japanese Black cattle.…”

Severe polyhydramnios as neonatal presentation of Bartter’s syndrome type IV

“…In most of them, the pregnancy was complicated due to polyhydramnios and they were born prematurely. In the subset of patients that was later available for genetic testing, Kurtz et al 9 identified a predominant mutation on the SCL12A1 gene, which is known to be cause of BS type I. 4,6,9,10 Birkenhäger et al 11 identified 7 different mutations in the BSND gene, and there have been reported more allelic variants.…”

“…In the subset of patients that was later available for genetic testing, Kurtz et al 9 identified a predominant mutation on the SCL12A1 gene, which is known to be cause of BS type I. 4,6,9,10 Birkenhäger et al 11 identified 7 different mutations in the BSND gene, and there have been reported more allelic variants. Besides, the same mutation may originate different clinical phenotypes, because of the individual variability in the genes of additional channels or in the modifying genes that regulate the expression.…”