XB-ART-13814
J Clin Invest
December 15, 1998;
102
(12):
2173-9.
Novel AE1 mutations in recessive distal renal tubular acidosis. Loss-of-function is rescued by glycophorin A.
Tanphaichitr VS
,
Sumboonnanonda A
,
Ideguchi H
,
Shayakul C
,
Brugnara C
,
Takao M
,
Veerakul G
,
Alper SL
.
Abstract
The
AE1 gene encodes
band 3 Cl-/HCO3- exchangers that are expressed both in the erythrocyte and in the acid-secreting, type A intercalated cells of the
kidney.
Kidney AE1 contributes to urinary acidification by providing the major exit route for HCO3- across the basolateral membrane. Several
AE1 mutations cosegregate with dominantly transmitted nonsyndromic renal tubular acidosis (dRTA). However, the modest degree of in vitro hypofunction exhibited by these dRTA-associated mutations fails to explain the disease phenotype in light of the normal urinary acidification associated with the complete loss-of-function exhibited by
AE1 mutations linked to dominant spherocytosis. We report here novel
AE1 mutations linked to a recessive syndrome of dRTA and hemolytic anemia in which red cell anion transport is normal. Both affected individuals were triply homozygous for two benign mutations M31T and K56E and for the loss-of-function mutation, G701D.
AE1 G701D loss-of-function was accompanied by impaired trafficking to the Xenopus
oocyte surface. Coexpression with
AE1 G701D of the erythroid
AE1 chaperonin, glycophorin A, rescued both
AE1-mediated Cl- transport and
AE1 surface expression in oocytes. The genetic and functional data both suggest that the homozygous
AE1 G701D mutation causes recessively transmitted dRTA in this kindred with apparently normal erythroid anion transport.
PubMed ID:
9854053
PMC ID:
PMC509172
Article link:
J Clin Invest
Grant support:
[+]
Species referenced:
Xenopus
Genes referenced:
hspd1
slc4a1
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