A new SLC12A3 founder mutation (p.Val647Met) in Gitelman's syndrome patients of Roma ancestry.
BACKGROUND
Gitelman's syndrome (GS) is an autosomal recessive disorder caused by mutations in the SLC12A3 gene. GS is characterized by hypokalaemic metabolic alkalosis, hypomagnesemia and hypocalciuria. Most of the reported patients of Roma ancestry are homozygous for an SLC12A3 intron 9 frameshifting mutation (c.1180+1G>T). Some forms of Bartter's syndrome result from mutations in the CLNCKB gene and clinically overlap with GS.


OBJECTIVE
To characterize a second SLC12A3 mutation in Roma patients negative for the intron 9 variant.


METHODS
SLC12A3 and CLNCKB genes were analyzed by next-generation sequencing in two Spanish and Greek gypsy patients who were negative for the intron 9 splicing mutation. Sanger sequencing was performed to confirm the putative mutations in patients and family members.


RESULTS
We identified a missense variant (p.Val647Met, c.1939G>A) in both cases, and both were homozygous for Met. This mutation was also found in three additional patients; two homozygous and one heterozygous compound with the intron 9 splicing mutation. This new SLC12A3 mutation seems to be characteristic of gipsy GS patients and was linked to the same haplotype in all cases, supporting a founder origin. All the patients showed biochemical features characteristic of GS.


CONCLUSIONS
We report a second founder mutation among GS patients of Roma ethnic background. The direct screening of this mutation would facilitate the characterization of patients who are negative for the more common intron 9 +1G>T mutation.
Dept. Pediatría-RENALTUBE Consortium, Hospital Universitario Central Asturias, Oviedo, Spain. Electronic address: hgilpena@gmail.com.
Helena
H
Gil-Peña
Dept. Genética Molecular-Red de Investigación Renal, Hospital Universitario Central Asturias, Oviedo, Spain; Hôpital Européen Georges Pompidou, France.
Eliecer
E
Coto
Dept. Pediatría-RENALTUBE Consortium, Hospital Universitario Central Asturias, Oviedo, Spain; Hôpital Européen Georges Pompidou, France.
Fernando
F
Santos
Hospital Doce de Octubre, Madrid, Spain.
Mar
M
Espino
Hospital Severo Ochoa, Leganés, Spain.
Jose Mª
JM
Cea Crespo
Dept. Pediatrics, Aghia Sophia Children's Hospital, Athens, Greece.
Giannis
G
Chantzopoulos
Dept. Pediatrics, Aghia Sophia Children's Hospital, Athens, Greece.
Filadelfia
F
Komianou
Dept. Genética Molecular-Red de Investigación Renal, Hospital Universitario Central Asturias, Oviedo, Spain.
Juan
J
Gómez
Dept. Genética Molecular-Red de Investigación Renal, Hospital Universitario Central Asturias, Oviedo, Spain.
Belén
B
Alonso
Dept. Genética Molecular-Red de Investigación Renal, Hospital Universitario Central Asturias, Oviedo, Spain.
Sara
S
Iglesias
Hôpital Européen Georges Pompidou, France.
Cyrielle
C
Treard
Hôpital Européen Georges Pompidou, France.
Rosa
R
Vargas-Poussou
Antecedentes genéticos gitanos; Gen SLC12A3; Gitelman's syndrome; Gypsy patients; Pacientes de etnia gitana; Roma genetic background; SLC12A3 gene; Síndrome de Gitelman