Gitelman's Syndrome (GS) is the most common primary renal tubular disorder, affecting approximately 1/40,000 Caucasians. GS is inherited as an autosomal recessive disease mainly linked to mutations in the SLC12A3 gene (solute carrier family 12 sodium/chloride transporters, member 3), that encodes a thiazide-sensitive sodium-chloride co-transporter (NCC) protein that locates at the luminal membrane of the distal convoluted tubule in the kidney.1 GS is characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria.2,3 The loss of function of the NCC channel leads to decreased sodium re-absorption and subsequently secondary volume depletion. The hypovolemia stimulates sodium re-absorption at the expense of increased potassium and hydrogen secretion, which results in hypokalemia and metabolic alkalosis.4 Hypocalciuria and hypomagnesaemia are also characteristic of GS, the latter being a likely consequence of the elevation of the excretion of magnesium in urine.5,6

Most of the GS patients are homozygous or heterozygous compound for rare private mutations. Due to the absence of common mutations, the sequencing of the full SLC12A3 is required to uncover the genetic background of GS patients.7 Moreover, some cases presenting as GS might carry mutations at the CLCNKB gene, a fact that increases the technical effort of the genetic study.7

The Roma or Gypsies represent the largest and most widespread ethnic minority in Europe. Anthropological and genetic data support their origin in the Indian subcontinent.8 Although there was some mixture with their hosting populations, consanguinity is common among Gypsies and results in the presence of founder-mutations for several inherited disorders.9 To date, most of the reported Gypsy patients having GS are homozygous for the intron 9 +1G>T mutation (c.1180+1G>T).10–12 Here, we describe a new SLC12A3 mutation characteristic of Roma SG patients.

More than 180 mutations in SLC12A3 gene have been reported in GS patients.7 There is not a prevalent mutation, and this means that the sequencing of the 26 SLC12A3 exons is required to search for mutations in most of the GS patients.15,16 Moreover, CLCNKB mutations may be found in some cases with clinical manifestations of GS, a fact that increases the complexity of the genetic study of GS. Thus, the discovery of mutations common in an ethnic group will facilitate the genetic analysis by limiting the sequencing to one or few exons.10

In this article we present Gypsy cases from Spain and Greece with the same mutation in the SLC12A3 gene. Patients were recruited through the Renaltube Consortium13 which collects data from patients worldwide in an attempt to better define the clinical profile and the genetic background of renal tubulopathies. To date, >50 Gypsi GS patients are included in the Renaltube database and most of these patients are homozygous for the intron 9 splicing mutation. The index cases of Families I and II, were subjected to NGS to search for new SLC12A3 mutations, resulting in the identification of p.Val647Met. The p.Val647Met variant was predicted to be pathogenic with at least two bioinformatic programs (SIFT and Polyphen). This missense change locates at the intracellular carboxy-end of the protein (Fig. 2), where other GS mutations have been found and aminoacids at this region are conserved not only among species but also in other human channels such us bumetanide-sensitive cotransporter (SLC12A2 gene).17

Fig. 2.

Map of the SLC12A3 showing the position of amino acid 647.

(0.23MB).

The p.Val647Met mutation had been previously reported by Vargas-Poussou et al. in one GS patient (PV.1) compound heteorzygous for this variant and the intron 9 mutation.7 Thus, the two families we studied and the three previously reported by Vargas et al.7 had a common Gipsy genetic background and traced their ancestry to South-Eastern Europe. The p.Val647Met was linked to the same SLC12A3 polymorphisms in the 5 families, a fact that strongly supports a common origin for this new Gipsy SG mutation.

In conclusion, we report a new SLC12A3 founder mutation among GS patients of Gypsy background, p.Val647Met. This mutation was associated with typical clinical features of GS, either in homozygosity or in combination with the intron 9+1G>A mutation. Our finding facilitates the diagnosis of GS in Gypsy patients.

All the patients/participants in the study gave their informed consent, approved by the Ethical Committee of Hospital Universitario Central Asturias.

The authors declare no conflict of interest.