Functional characterization of wild-type and a mutated form of SLC26A4 identified in a patient with Pendred syndrome.
BACKGROUND
Malfunction of the SLC26A4 protein leads to prelingual deafness often associated with mild thyroid dysfunction and goiter. It is assumed that SLC26A4 acts as a chloride/anion exchanger responsible for the iodide organification in the thyroid gland, and conditioning of the endolymphatic fluid in the inner ear.


METHODS
Chloride uptake studies were made using HEK293-Phoenix cells expressing human wild type SLC26A4 (pendrin) and a mutant (SLC26A4(S28R)) we recently described in a patient with hypothyroidism, goiter and sensorineural hearing loss.


RESULTS
Experiments are summarized showing the functional characterization of wild type SLC26A4 and a mutant (S28R), which we described recently. This mutant protein is transposed towards the cell membrane, however, its transport capability is markedly reduced if compared to wild-type SLC26A4. Furthermore, we show that the SLC26A4 induced chloride uptake in HEK293-Phoenix cells competes with iodide, and, in addition, that the chloride uptake can be blocked by NPPB and niflumic acid, whereas DIDS is ineffective.


CONCLUSIONS
The functional characteristics of SLC26A4(S28R) we describe here, are consistent with the clinical phenotype observed in the patient from which the mutant was derived.
Dossena
Silvia
S
Department of Biomolecular Sciences and Biotechnology, Università degli Studi di Milano, Italy.
Vezzoli
Valeria
V
Cerutti
Nadia
N
Bazzini
Claudia
C
Tosco
Marisa
M
Sironi
Chiara
C
Rodighiero
Simona
S
Meyer
Giuliano
G
Fascio
Umberto
U
Fürst
Johannes
J
Ritter
Markus
M
Fugazzola
Laura
L
Persani
Luca
L
Zorowka
Patrick
P
Storelli
Carlo
C
Beck-Peccoz
Paolo
P
Bottà
Guido
G
Paulmichl
Markus
M
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D006042:Goiter / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics*; D007454:Iodides / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D009544:Niflumic Acid / Q000494:pharmacology; D009579:Nitrobenzoates / Q000494:pharmacology; D000076988:Sulfate Transporters; D013577:Syndrome
D002712:Chlorides; D007454:Iodides; D026901:Membrane Transport Proteins; D009579:Nitrobenzoates; C085609:SLC26A4 protein, human; D000076988:Sulfate Transporters; C058176:5-nitro-2-(3-phenylpropylamino)benzoic acid; D009544:Niflumic Acid; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid