Novel mutations in the SLC12A3 gene causing Gitelman's syndrome in Swedes.
OBJECTIVE
Gitelman's syndrome (GS) is an inherited autosomal recessive disorder due to loss of function mutations in the SLC12A3 gene encoding the Na-Cl co-transporter (NCCT), the target of thiazide diuretics. The defective function of the NCCT, which normally is expressed in the apical membrane of the distal convolute tubule in the kidney, leads to mild hypotension, hypokalemia, hyperreninemic hyperaldosteronism, mild metabolic alkalosis, hypomagnesemia and hypocalciuria. Up to now, more than 100 mutations of the SLC12A3 gene have been described in GS patients.


METHODS
We have collected 30 patients from Sweden with a clinical diagnosis of GS and undertaken a mutation screening by SSCP and successive sequencing of the 26 exons and intronic boundaries. Both mutations were identified in most (n = 28, 93%) and at least one mutation was identified in all patients.


RESULTS
We found 22 different mutations evenly distributed throughout the gene, 11 of which have not been described previously. The new variants include 8 missense mutations (Glu68Lys, His69Asn, Argl45His, Vall53Met, Gly230Asp, Gly342Ala, Val677Leu and Gly867Ser), 1 insertion (c.834_835insG on exon 6) and 2 splice-site mutations (c.2667 + lT>G substitution in splicing donor site after exon 22, c.1569-1G>A substitution in the splicing acceptor site before exon 13).


CONCLUSIONS
In Swedish patients with the clinical features of GS, disease-causing mutations in the SLC12A3 gene were identified in most patients. The spectrum of GS mutations is wide making full mutation screening of the SLC12A3 gene necessary to confirm the diagnosis.
Fava
Cristiano
C
Division of Endocrinology, Department of Clinical Sciences, University of Malmö, Malmo, Sweden. christiano.fava@med.lu.se
Montagnana
Martina
M
Rosberg
Lena
L
Burri
Philippe
P
Jönsson
Anders
A
Wanby
Pär
P
Wahrenberg
Hans
H
Hulthén
U Lennart
UL
Aurell
Mattias
M
Guidi
Gian Cesare
GC
Melander
Olle
O
D017668:Age of Onset; D005091:Exons; D005808:Genes, Recessive; D005820:Genetic Testing; D014644:Genetic Variation; D053579:Gitelman Syndrome / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics* / Q000503:physiopathology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007438:Introns; D008957:Models, Genetic; D016254:Mutagenesis, Insertional; D009154:Mutation; D020125:Mutation, Missense; D018807:Polymorphism, Single-Stranded Conformational; D022821:RNA Splice Sites / Q000235:genetics; D011955:Receptors, Drug / Q000235:genetics*; D064486:Solute Carrier Family 12, Member 3; D013548:Sweden; D027981:Symporters / Q000235:genetics*
D022821:RNA Splice Sites; D011955:Receptors, Drug; C578874:SLC12A3 protein, human; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters