Novel NCCT gene mutations as a cause of Gitelman's syndrome and a systematic review of mutant and polymorphic NCCT alleles.
BACKGROUND
Gitelman's syndrome (GS) is characterized by hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria and these phenotypic features have been shown to be attributable to mutations in the gene encoding the thiazide-sensitive Na/Cl cotransporter (NCCT). Until now, 55 different mutations have been reported and most of the families affected with GS exhibit autosomal recessive inheritance.


METHODS
All 26 exons of the human NCCT gene were investigated in 2 German NCCT-deficient patients and their families. Mutation detection was performed by either direct automated sequencing of polymerase chain reaction (PCR)-amplified DNA products or by sequence analysis of cloned PCR products.


RESULTS
In a 47-year-old German GS female a novel non-conservative missense mutation (S314F) and a complex deletion/insertion in the NCCT gene were found to be associated with the disorder. A further novel non-conservative substitution (S402F) together with a frequently observed R209W exchange were found in a 19-year-old German GS female.


CONCLUSIONS
The observation of a compound heterozygote state in both females affected and the absence of a GS phenotype in their relatives carrying a single mutant allele is consistent with an autosomal recessive pattern of inheritance.
Reissinger
Annette
A
Department of Clinical Biochemistry, Medizinische Poliklinik, Division of Nephrology, University of Bonn, Germany.
Ludwig
Michael
M
Utsch
Boris
B
Prömse
Astrid
A
Baulmann
Johannes
J
Weisser
Burkhard
B
Vetter
Hans
H
Kramer
Herbert J
HJ
Bokemeyer
Dirk
D
D000328:Adult; D000471:Alkalosis / Q000235:genetics*; D000595:Amino Acid Sequence; D002118:Calcium / Q000652:urine; D002352:Carrier Proteins / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D006579:Heterozygote; D006801:Humans; D007008:Hypokalemia / Q000235:genetics*; D008274:Magnesium / Q000097:blood; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D011955:Receptors, Drug; 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; D008274:Magnesium; D002118:Calcium