Functional characterization of wild-type and mutated pendrin (SLC26A4), the anion transporter involved in Pendred syndrome
- Silvia Dossena1,
- Simona Rodighiero2,
- Valeria Vezzoli1,3,
- Charity Nofziger1,
- Elisabetta Salvioni1,3,
- Marta Boccazzi1,3,
- Elisabeth Grabmayer1,
- Guido Bottà3,
- Giuliano Meyer3,
- Laura Fugazzola4,5,
- Paolo Beck-Peccoz4,5 and
- Markus Paulmichl1
- 1Institut of Pharmacology and Toxicology, Paracelsus Medical University, A-5020 Salzburg, Austria
2CIMAINA,
3Department of Biomolecular Sciences and Biotechnology
4Department of Medical Sciences, Università degli Studi di Milano, I-20133 Milan, Italy
5Endocrine and Diabetes Unit, Fondazione Policlinico, IRCCS, I-20122 Milan, Italy
- (Correspondence should be addressed to M Paulmichl; Email: markus.paulmichl{at}pmu.ac.at)
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Figure 1
Cell model of the ion transport mechanisms in follicular cells of the thyroid gland. The sodium/potassium ATPase and the sodium/iodide symporter (NIS) are located on the basolateral side of follicular cells. At the apical side, pendrin is responsible for iodide transport into the follicules. However, an additional unknown iodide transporter may be expressed in the apical membrane.
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Figure 2
Enlarged vestibular aqueduct (EVA) and enlarged endolymphatic sac in PS patients. Computed tomographic (CT)-image (left), and a magnetic resonance image (MRI; right) of the temporal bone of two PS patients with EVA are indicated by an arrow in the CT-image, while the MRI shows an enlarged endolymphatic sac.
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Figure 3
Sequence comparison of SLC26A4 in different species. (1) Homo sapiens (NP_000432), (2) Rattus norvegicus (NP_062087), (3) Mus musculus (NP_035997), (4) Pan troglodytes (XP_519308), (5) Macaca mulatta (XP_001094049), (6) Canis familiaris (XP_540382), (7) Bos taurus (XP_608706), (8) Monodelphis domestica (XP_001363598), (9) Gallus gallus (XP_425419), (10) Danio rerio (XP_692273), and (11) Xenopus laevis (NP_001089008). The 15 putative trans-membrane (TM) helices are indicated with arrows and respective numbering (S1–S15). The two amphipathic helices are boxed in red, and the STAS-domain is boxed in blue. The sulfate-transport-consensus-signature is boxed in green, and the glycine repeat is indicated in yellow.
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Figure 4
Putative topology of human pendrin. (a) The 12 TM model as described on the Pendred/BOR homepage (http://www.healthcare.uiowa.edu/labs/pendredandbor/domains.htm) using the MEMSAT program. (b) The 15 TM-segment model as proposed in this review. The amino terminus in this model would be located on the extracellular side, and the carboxy terminus would be located at the cytoplasmic side. The 15 trans-membrane (TM) segments are depicted as stretches of amino acids crossing the membrane, which is shown in grey. The position of the TM helices with respect to the membrane (the part of the putative helix that is exposed to the lipid moiety of the membrane) is tentative. The color code of the boxes is equal to that in Fig. 3. It is important to mention that both models are speculative; however, the two models depicted here will help to design experiments, which are needed in order to define the real nature and position of the different TM units.
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Figure 5
Topology of the functionally characterized SLC26A4 mutations. The putative model is taken from Fig. 4 and the respective mutations are indicated. Light blue indicates the mutations with no functional impact, i.e. those mutations indistinguishable from wild-type. In orange are those mutations with a reduced function and in red are those mutations leading pendrin un-functional. The extension ‘X’ indicates the mutations that lead to a truncation in the SLC26A4 sequence. *Allelic variants described as polymorphisms but whose functionality is not unambiguous (Choi et al. 2008).
- © 2009 Society for Endocrinology
