| Literature References | 1. GAMBA, G., SALTZBERG, S.N., LOMBARDI, M., MIYANOSHITA, A., LYTTON, J.,
HEDIGER, M.A., BRENNER, B.M. AND HEBERT, S.C.
Primary structure and functional expression of a cDNA encoding the thiazide
PROC.NATL.ACAD.SCI.U.S.A. 90 2749-2753 (1993).
2. MOUNT, D.B., DELPIRE, E., GAMBA, G., HALL, A.E., POCH, E., HOOVER, R.S.,
AND HEBERT, S.C.
The electroneutral cation-chloride cotransporters.
J.EXP.BIOL. 201 2091-2102 (1998).
3. SIMON, D.B., NELSON-WILLIAMS, C., BIA, M.J., ELLISON, D., KARET, F.E.,
MOLINA, A.M., VAARA, I., IWATA, F., CUSHNER, H.M., KOOLEN, M., GAINZA,
F.J., GITELMAN, H.J. AND LIFTON, R.P.
Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis,
is caused by mutations in the thiazide-sensitive Na-Cl cotransporter.
NAT.GENET. 12 24-30 (1996).
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| Documentation | The thiazide-sensitive Na-Cl co-transporter is a large integral membrane
protein (~1000 amino acids) that mediates the coupled transport of Na+ and
Cl- in an electrically silent manner. In the mammalian kidney, it is the
dominant mechanism mediating Cl- absorption in the early distal tubule, and
here it is the target of the widely-used thiazide class of diuretic drugs.
It is also known to be present in the urinary bladder of the winter
flounder, from where the gene encoding it was initially cloned [1].
Hydrophobicity analysis predicts the Na-Cl co-transporter to have 12
transmembrane (TM) domains and comparisons with other cloned ion co-
transporters reveals that a superfamily of electroneutral cation-chloride
co-transporters exists, which includes the K-Cl co-transporters (PR01081)
and the Na-K-Cl co-transporters (PR01207). All share a similar predicted
membrane topology in a central hydrophobic domain, together with
hydrophilic N- and C-termini that are likely cytoplasmic [2].
Mutations in the thiazide-sensitive Na-Cl co-transporter have been
found that give rise to Gitelman's variant of Bartter's syndrome,
an inherited kidney disease characterised by hypokalaemic alkalosis [3].
NACLTRNSPORT is a 4-element fingerprint that provides a signature for
thiazide-sensitive Na-Cl co-transporters. The fingerprint was derived from
an initial alignment of 3 sequences: the motifs were drawn from conserved
regions spanning virtually the full alignment length - motif 1 lies at the
start of the fifth putative TM domain; motif 2 encodes ~1/3 of the seventh
TM domain; motif 3 encodes a short portion of the putative cytoplasmic loop
between TM domains 8 and 9; and motif 4 lies at the end of the cytoplasmic
C-terminus. Two iterations on SPTR37_10f were required to reach convergence,
at which point a true set comprising 5 sequences was identified.
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