Downregulated in adenoma gene encodes a chloride transporter defective in congenital chloride diarrhea.
Congenital chloride diarrhea (CLD) is a recessively inherited disorder characterized by massive loss of chloride in stool. We previously identified mutations in the downregulated in adenoma (DRA) gene in patients with CLD and demonstrated that DRA encodes an intestine-specific sulfate transporter. To determine whether DRA is an intestinal chloride transporter and how mutations affect transport, Xenopus oocytes were injected with wild-type and mutagenized DRA cRNA and uptake of Cl- and SO2-4 was assayed. Both Cl- and SO2-4 were transported by wild-type DRA and an outwardly directed pH gradient stimulated Cl- uptake, consistent with Cl-/OH- exchange. Among three mutants, C307W transported both anions as effectively as wild-type, whereas transport activity was lost in V317del and the double mutant identified in 32 of 32 Finnish CLD patients. We conclude that DRA is a chloride transporter defective in CLD and that V317del is a functional mutation and C307W a silent polymorphism.
Moseley
R H
RH
Department of Internal Medicine, Veterans Affairs Medical Center and University of Michigan School of Medicine, Ann Arbor, Michigan 48105, USA.
Höglund
P
P
Wu
G D
GD
Silberg
D G
DG
Haila
S
S
de la Chapelle
A
A
Holmberg
C
C
Kere
J
J
D000818:Animals; D017920:Antiporters; D001692:Biological Transport / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D027963:Chloride-Bicarbonate Antiporters; D002712:Chlorides / Q000378:metabolism* / Q000493:pharmacokinetics; D003967:Diarrhea / Q000151:congenital / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D009154:Mutation / Q000502:physiology; D009865:Oocytes; D011110:Polymorphism, Genetic; D000076988:Sulfate Transporters; D013431:Sulfates / Q000493:pharmacokinetics; D014982:Xenopus laevis
D017920:Antiporters; D002352:Carrier Proteins; D027963:Chloride-Bicarbonate Antiporters; D002712:Chlorides; D008565:Membrane Proteins; C081011:SLC26A3 protein, human; D000076988:Sulfate Transporters; D013431:Sulfates