A new mutation (intron 9 +1 G>T) in the SLC12A3 gene is linked to Gitelman syndrome in Gypsies.
BACKGROUND
Gitel syndrome is an inherited tubular disorder characterized by metabolic alkalosis, hypokalemia, and hypomagnesemia of renal origin and hypocalciuria. The majority of patients with Gitelman syndrome carry inactivating mutations in the SLC12A3 gene encoding the sodium-chloride cotransporter located in the distal convoluted tubule. The purpose of this study was to investigate the underlying mutation in Gitelman syndrome patients of Gypsy race from different geographic origin.


METHODS
Twenty Gypsy patients with clinical and biochemical features of Gitelman syndrome were investigated by mutational analysis. The patients belonged to 12 unrelated Gypsy families living in four different European countries. The parents and unaffected siblings of each patient, as well as the DNA of a population of 200 healthy control patients, were also analyzed.


RESULTS
All patients were homozygous for the same splice site mutation, guanine to thymine in the first position of intron 9 of SLC12A3 gene. This mutation was not found in the control population. Parents were heterozygous for the mutation. Despite sharing a common mutation, the clinical manifestations of the syndrome in the patients varied from lack of symptoms in six children to severe growth retardation in four.


CONCLUSIONS
Demonstration of a novel point mutation within the SLC12A3 gene in our cohort of Gypsy families with Gitelman syndrome is highly suggestive of a founder effect. This finding will facilitate the identification of the genetic defect in further cases of Gitelman syndrome among the Gypsy population. Our study represents the largest series ever published of patients with Gitelman syndrome having the same underlying mutation, and supports the lack of correlation between genotype and clinical phenotype in this disease.
Coto
Eliecer
E
Hospital Universitario Central de Asturias, Spain.
Rodriguez
Julian
J
Jeck
Nikola
N
Alvarez
Victoria
V
Stone
Rosario
R
Loris
Cesar
C
Rodriguez
Luis M
LM
Fischbach
Michel
M
Seyberth
Hannsjörg W
HW
Santos
Fernando
F
D000293:Adolescent; D000328:Adult; D000471:Alkalosis / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D018703:Founder Effect; D005838:Genotype; D006801:Humans; D007008:Hypokalemia / Q000235:genetics*; D007223:Infant; D007438:Introns / Q000235:genetics; D007674:Kidney Diseases / Q000235:genetics*; D008275:Magnesium Deficiency / Q000235:genetics; D008297:Male; D017354:Point Mutation; D012150:Polymorphism, Restriction Fragment Length; D011955:Receptors, Drug / Q000235:genetics*; D006178:Romani People / Q000235:genetics*; D049992:Sodium Chloride Symporters; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters
D002352:Carrier Proteins; D011955:Receptors, Drug; C578874:SLC12A3 protein, human; D049992:Sodium Chloride Symporters; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; C064415:thiazide receptor