Genetics and phenomics of Pendred syndrome

Molecular and Cellular Endocrinology 322 (2010) 83–90

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Molecular and Cellular Endocrinology journal homepage: www.elsevier.com/locate/mce

Review

Genetics and phenomics of Pendred syndrome Aigerim Bizhanova, Peter Kopp ∗ Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Tarry 15, 303 East Chicago Avenue, Chicago, IL 60611, USA

a r t i c l e

i n f o

Article history: Received 12 August 2009 Received in revised form 7 March 2010 Accepted 8 March 2010 Keywords: Pendred syndrome Pendrin SLC26A4 Deafness Goiter Thyroid hormone

a b s t r a c t Pendred syndrome is an autosomal recessive disorder characterized by sensorineural deafness, goiter and a partial defect in iodide organification. Goiter development and hypothyroidism vary and appear to depend on nutritional iodide intake. Pendred syndrome is caused by biallelic mutations in the SLC26A4 gene, which encodes pendrin, a multifunctional anion exchanger. Pendrin is mainly expressed in the thyroid, the inner ear, and the kidney. In the thyroid, pendrin localizes to the apical membrane of thyrocytes, where it may be involved in mediating iodide efflux. Loss-of-function mutations in the SLC26A4 gene are associated with a partial iodide organification defect, presumably because of a reduced iodide efflux into the follicular lumen. In the kidney, pendrin functions as a chloride/bicarbonate exchanger. In the inner ear, pendrin is important in the maintenance of a normal anion transport and the endocochlear potential. Elucidation of the function of pendrin has provided unexpected novel insights into the pathophysiology of thyroid hormone biosynthesis, chloride retention in the kidney, and composition of the endolymph. © 2010 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5. 6. 7. 8. 9.

Pendred syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The SLC26A4 gene and pendrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The function of pendrin in the thyroid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Expression and regulation of pendrin in the thyroid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mutations of pendrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The function of pendrin in the inner ear . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The role of pendrin in the kidney . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pendrin in other tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Pendred syndrome Pendred syndrome (OMIM 274600) is an autosomal recessive disorder characterized by sensorineural deafness, goiter, and a partial defect in iodide organification. The association of goiter and deafness was first described by Vaughan Pendred in 1896 (Pendred, 1896). Morgans and Trotter then first demonstrated that patients with Pendred syndrome have a partial iodide organification defect (Morgans and Trotter, 1958). Pendred syndrome is one of the most common forms of syndromic deafness. The incidence of Pendred syndrome is estimated to be as high as 7.5 to 10 in 100,000 indi-

∗ Corresponding author. Tel.: +1 312 503 1394; fax: +1 312 908 9032. E-mail address: [email protected] (P. Kopp). 0303-7207/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mce.2010.03.006

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viduals, thus accounting for up to 10% of all hereditary hearing loss (Reardon et al., 1997; Fraser, 1965). The sensorineural deafness is the leading clinical sign of Pendred syndrome (Morgans and Trotter, 1958; Kopp et al., 2008). Typically, the hearing loss is profound and prelingual. However, in some individuals, hearing impairment may develop later in childhood and then progress (Reardon et al., 1997; Cremers et al., 1998). The hearing loss may fluctuate and it has been shown to progress following even minor head trauma (Colvin et al., 2006; Luxon et al., 2003). Deafness is accompanied by malformations of the inner ear, which can be identified by computed tomography or magnetic resonance imaging (Fugazzola et al., 2000). These malformations include an enlargement of the endolymphatic system that can be detected as an enlarged vestibular aqueduct (EVA; ≥1.5 mm) on imaging studies (Fig. 1) (Reardon et al., 1997; Fugazzola et al., 2000; Phelps et

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Fig. 1. Enlarged vestibular aqueduct. Computer tomography of the right temporal bone of a child with Pendred’s syndrome. EVA = enlarged vestibular aqueduct. IAC = internal acoustic channel. LSC = lateral semicircular channel.

al., 1998). Some patients have a Mondini cochlea, in which the coils of the cochlea are replaced by a single cavity (Reardon et al., 1997; Phelps et al., 1998). The Mondini dysplasia is, however, not specific for Pendred syndrome as it can be observed in several other disorders (Pryor et al., 2005). The onset and presentation of goiter varies within and between families. It usually develops during childhood and ranges from no enlargement of the thyroid to the development of large goiters (Fraser, 1965; Fraser et al., 1960). When evaluated with a perchlorate test, all patients with biallelic mutations in the SLC26A4 gene have a partial iodide organification defect, irrespective of the presence or absence of a goiter (Pryor et al., 2005). The perchlorate test determines whether iodide is organified normally into thyroglobulin (TG) (Baschieri et al., 1963). Normally, less than 10% of radioiodide accumulated in thyrocytes are not rapidly organified into thyroglobulin for the purpose of thyroid hormone synthesis (see later). In contrast, patients with Pendred syndrome loose more than 15% thus indicating an impaired iodide organification (Morgans and Trotter, 1958; Reardon et al., 1997). However, the organification defect is only partial (Morgans and Trotter, 1958; Pryor et al., 2005; Gillam et al., 2004). This differs, for example, from the situation in patients who are homozygous for completely inactivating mutations in thyroid peroxidase that result in a total iodide organification defect (Kopp, 2005). Despite the presence of a partial iodide organification defect, patients with Pendred syndrome only develop hypothyroidism under conditions of a low nutritional iodide intake (Fraser, 1965; Nilsson et al., 1964; Trotter, 1960; Gausden et al., 1997; Sato et al., 2001). For example, patients from Japan and Korea (countries with a high iodide intake) with documented biallelic mutations in the SLC26A4 gene are always euthyroid (Park et al., 2005, 2003; Tsukamoto et al., 2003). In contrast, patients with Pendred syndrome from iodide-deficient regions may present with congenital hypothyroidism (Gonzalez Trevino et al., 2001). Many patients have elevated serum levels of thyroglobulin, a finding that correlates with goiter size (Sheffield et al., 1996; Medeiros-Neto and Stanbury, 1994). It should also be noted that phenocopies of Pendred syndrome, i.e. deafness due to another etiologic cause in combination with goiter due to iodide deficiency, have been reported (Kopp et al., 1999). Of note, EVA is associated with syndromic and non-syndromic forms of sensorineural deafness (Pryor et al., 2005). The diagnosis of Pendred syndrome in patients with EVA can be formally established by the demonstration of an iodide organification defect through the perchlorate test, while goiter is a more variable sign and dependent on iodide intake. Pendred syndrome is caused by biallelic mutations in the SLC26A4 gene, which encodes the multifunctional anion exchanger pendrin (Everett et al., 1997). All patients with biallelic mutations

in the SLC26A4 gene have Pendred syndrome, indicating that it is genetically homogeneous (Table 1) (Pryor et al., 2005). The recessive form of hearing loss referred to as DFNB4 (OMIM 600791), originally thought to be a distinct entity because of the absence of an enlarged thyroid, is also explained by mutations in the SLC26A4 gene and is thus allelic with Pendred syndrome (Table 1). Patients with DFNB4 display sensorineural hearing loss with an EVA and, if formally tested, they have a positive perchlorate test despite the absence of an enlarged thyroid (Campbell et al., 2001). Patients with non-syndromic EVA are either homozygous for the SLC26A4 wildtype, or they have only one mutated allele (Pryor et al., 2005; Azaiez et al., 2007; Pera et al., 2008a). In some families, non-syndromic EVA is associated with monoallelic SLC26A4 mutations suggesting that unrecognized mutations in other regions of the gene or in another gene could contribute to the pathogenesis of the phenotype (Pryor et al., 2005). Double heterozygosity for mutations in the SLC26A4 gene and the transcription factor FOXI1, which is involved in the regulation of SLC26A4 gene expression, has been reported in a family with EVA as well as in double heterozygous mice (Slc26A4+/− ; Foxi1+/− ) (Table 1) (Yang et al., 2007). This observation confirms that Pendred syndrome and non-syndromic EVA may have a digenic cause in a subgroup of patients (Yang et al., 2007). The recent finding of digenic mutations in SLC26A4 and KCNJ10, a potassium channel involved in the generation of the endocochlear potential, in patients with EVA further support that this phenotype can have a oligo- or polygenic etiology (Table 1) (Yang et al., 2009).

2. The SLC26A4 gene and pendrin Pendrin is a member of the solute carrier family 26A (SLC26A) (Everett and Green, 1999). With the exception of the motor protein prestin, which is expressed in outer hair cells, all members of this family function as anion exchangers (Everett and Green, 1999; Dawson and Markovich, 2005; Zheng et al., 2000). The two human genes most closely related to pendrin based on sequence comparisons are DRA (downregulated in adenoma, SLC26A3) and DTD (diastrophic dystrophia, SLC26A2) (Hastbacka et al., 1994; Hoglund et al., 1996). SLC26A3/DRA encodes a chloride/sulfate transporter, which is highly expressed in the intestine and the prostate (Hoglund et al., 1996; Silberg et al., 1995). The gene encoding SLC26A3/DRA is located in a tail-to-tail orientation in close proximity to the SLC26A4 gene, suggesting a common ancestral gene (Fig. 2) (Kopp, 1999a). Mutations in the DRA/SLC26A3 gene cause congenital chloride diarrhea (Hoglund et al., 1996). SLC26A2/DTD is a sulfate transporter that is mostly expressed in the intestine and cartilage; mutations in this gene cause a spectrum of chondrodysplasias (Satoh et al., 1998). The SLC26A4 gene consists of 21 exons and is located on chromosome 7 (Fig. 2) (Everett et al., 1997). Pendrin is a 73 kDa membrane protein comprised of 780 amino acids (Scott and Karniski, 2000; Royaux et al., 2000). It is predicted to have 12 putative transmembrane domains with both the amino- and carboxy-termini located inside the cytosol (Fig. 2) (Royaux et al., 2000; Gillam et al., 2005). Pendrin has a sulfate transporter domain and a STAS (sulfate transporter and antisigma factor antagonist) domain (Aravind and Koonin, 2000). The STAS domain has been suggested to play a role in nucleotide binding or to interact with other proteins such as the cystic fibrosis conductance regulator (CFTR) (Aravind and Koonin, 2000; Shcheynikov et al., 2006; Ko et al., 2004, 2002). Its exact role, however, remains unknown. Pendrin is able to mediate exchange of chloride with bicarbonate, formate, and iodide (Scott and Karniski, 2000; Everett, 2006; Soleimani et al., 2001; Scott et al., 1999). Pendrin is mostly abundantly expressed in the thyroid, the inner ear, and the kidney (Royaux et al., 2000; Soleimani et al., 2001; Everett et al., 1999). In

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Table 1 Clinical presentation and molecular cause of Pendred syndrome and non-syndromic enlarged vestibular aqueduct (EVA). Pendred syndrome

EVA with positive perchlorate test

EVA with negative perchlorate test

EVA iodide organification unknown

Inner Ear

Sensorineural deafness EVA (displastic cochlea)

Sensorineural deafness EVA (displastic cochlea)

Sensorineural deafness EVA (displastic cochlea)

Sensorineural deafness EVA (Displastic cochlea)

Thyroid

Goiter

Normal size

Normal size

Normal size

Iodide organification

Positive perchlorate test

Positive perchlorate test

Molecular cause

Biallelelic mutations in SLC26A4

the thyroid, pendrin is localized at the apical membrane of thyroid follicular cells and appears to be involved in mediating iodide efflux into the follicular lumen (see later) (Gillam et al., 2004; Royaux et al., 2000; Yoshida et al., 2002, 2004). In the inner ear, pendrin is found in the endolymphatic duct and sac, where it acts as a chloride/bicarbonate exchanger (Everett et al., 1999; Royaux et al., 2003). Recent studies using the Pds/Slc26a4 knockout mouse reveal that pendrin plays a role in fluid transport in the inner ear and generation of the endocochlear potential (Everett et al., 1999; Royaux et al., 2003; Wangemann et al., 2004). In the kidney, pendrin resides on the apical membrane of intercalated type B cells, and in intercalated type non-A-non-B cells of the cortical collecting duct and the connecting tubules (Soleimani et al., 2001; Royaux et al., 2001). Pendrin has been shown to play a role in the electrolyte balance by mediating bicarbonate secretion (Royaux et al., 2001), as well as in the regulation of blood pressure by modulating renal chloride absorption (see later) (Verlander et al., 2003; Quentin et al., 2004).

Negative perchlorate test

Not determined

Other etiology

1. Biallelelic mutations in SLC26A4 (autosomal recessive deafness DFNB4) 2. Double heterozygosity: SLC26A4+/− ; FOXI1+/− 3. Double heterozygosity: SLC26A4+/− ; KCNJ10+/−

3. The function of pendrin in the thyroid Thyroid hormone synthesis takes place in the thyroid follicles, which form the functional unit of the thyroid (Kopp, 2005). Uptake of iodide occurs at the basolateral membrane of thyrocytes and is mediated by the sodium-iodide symporter (NIS) (Dohan et al., 2003) in a process that depends on the sodium gradient generated by the Na+ /K+ -ATPase (Wolff, 1964). Once iodide has entered the follicular lumen, it is oxidized at the cell-colloid interface and rapidly organified by incorporation into selected tyrosyl residues of thyroglobulin (TG). This reaction, referred to as organification, is catalyzed by thyroid peroxidase (TPO) in the presence of hydrogen peroxide, and results in the formation of mono- and diiodotyrosines (MIT, DIT). In the subsequent coupling reaction, which is also catalyzed by TPO, two iodotyrosines are coupled to form either T4 or T3. In order to release thyroid hormones, thyroglobulin is engulfed by pinocytosis, digested in lysosomes, and then secreted into the bloodstream at the basolateral membrane

Fig. 2. Chromosomal location and structure of the SLC26A4/PDS and the SLC26A3/DRA genes, and current model of the secondary structure of the pendrin protein. Y = Nglycosylations sites. STAS = sulfate transporter and antisigma factor antagonist domain.

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through mechanisms that remain to be defined. Unused MIT and DIT are subjected to deiodination by an intracellular iodotyrosine dehalogenase (DEHAL1) (Moreno, 2003; Moreno et al., 2008), which results in the release of iodide that can be recycled for thyroid hormone synthesis (Kopp, 2005). Although the mechanisms regulating iodide uptake at the basolateral membrane of thyroid cells have been extensively explored (Dohan et al., 2003), much less is known about the apical iodide efflux into the follicular lumen. Electrophysiological studies characterizing iodide efflux in inverted plasma membrane vesicles suggested the existence of two apical iodide channels (Golstein et al., 1992). The expression of pendrin at the apical membrane of thyrocytes and its ability to transport iodide suggest that pendrin may be one of these iodide channels that regulate apical iodide efflux in the thyroid. Moreover, the partial iodide organification defect observed in patients with biallelic SLC26A4 mutations is consistent with a potential role of pendrin in thyroid hormone biosynthesis. Pendrin was originally proposed to function as a sulfate transporter based on its sequence homology to known sulfate transporters and the presence of a sulfate transporter motif (Everett et al., 1997). In initial functional studies of pendrin in Xenopus oocytes have shown that pendrin is unable to transport sulfate but instead mediates uptake of chloride and iodide in a sodium-independent manner (Scott et al., 1999). The ability of pendrin to mediate iodide efflux has been supported by a number of studies using heterologous expression systems, including non-polarized (Gillam et al., 2004; Yoshida et al., 2002, 2004; Taylor et al., 2002) and polarized cells (Gillam et al., 2004). Yoshida et al. (2002) have demonstrated that iodide efflux is much higher in non-polarized Chinese hamster ovary cells co-expressing NIS and pendrin compared to cells expressing NIS alone. Electrophysiological studies of COS-7 cells transfected with pendrin revealed that iodide efflux is more efficient under high extracellular iodide concentrations suggesting the possibility of iodide/chloride exchange (Yoshida et al., 2004). Findings obtained in polarized Madin–Darby canine kidney (MDCK) cells also support the concept that pendrin plays a role in facilitating vectorial iodide transport at the apical membrane (Gillam et al., 2004). The physiological role of pendrin in mediating apical iodide transport has, however, been questioned based on the following arguments. Targeted disruption of pendrin in knockout mice does not lead to the development of a goiter or abnormal thyroid hormone levels, at least under conditions of sufficient iodide intake (Everett et al., 2001). There are no functional data demonstrating a role of pendrin in iodide transport in vivo. Pendrin has a distinct role as a chloride/bicarbonate exchanger in the kidney (Soleimani et al., 2001; Royaux et al., 2001), and the inner ear (Everett, 2006; Everett et al., 1999). Patients with biallelic mutations in the SLC26A4 gene have only a mild or no thyroidal phenotype under normal iodide intake conditions (Sato et al., 2001); therefore, it is conceivable that other iodide channels and/or transporters are involved in the apical transport of iodide. Accordingly, other proteins have been proposed to mediate apical iodide efflux. Specifically, they include SLC5A8 and the chloride channel 5, ClCn5 (Paroder et al., 2006; Rodriguez et al., 2002). However, SLC5A8 (originally designated as human apical iodide transporter (hAIT) (Rodriguez et al., 2002)) is not involved in mediating apical iodide efflux as demonstrated by functional studies in Xenopus oocytes and polarized MDCK cells (Paroder et al., 2006). Localization of the ClCn5 protein at the apical membrane of thyrocytes and the development of a thyroidal phenotype in ClCn5-deficient mice that is similar to Pendred syndrome, suggests that ClCn5 could participate in mediating apical iodide efflux or iodide/chloride exchange (van den Hove et al., 2006). Although ClCn5 knockout mice display a thyroidal phenotype, it is important to recognize that patients with Dent syndrome do not develop a goi-

ter (van den Hove et al., 2006). For these reasons, further functional studies are needed to characterize the functional role of ClCn5 in the thyroid. Slc26a4 knockout mice have normal thyroid hormone levels but interestingly the follicular pH is reduced suggesting that pendrin is involved in bicarbonate transport at the apical membrane of thyrocytes (Wangemann et al., 2009). The physiological significance of the acidification of the follicular lumen awaits further characterization. 4. Expression and regulation of pendrin in the thyroid The efflux of iodide across the apical membrane of thyrocytes is stimulated by TSH through activation of the cAMP pathway (Nilsson et al., 1990, 1992; Weiss et al., 1984). Several studies in polarized porcine thyrocytes (Nilsson et al., 1990, 1992) and in FRTL-5 cells (Weiss et al., 1984) revealed a rapid increase in iodide efflux into the follicular lumen following an acute exposure to the TSH. Nilsson et al. (1990) explored iodide efflux in polarized porcine thyrocytes cultured in bicameral chambers and demonstrated that TSH upregulates iodide efflux selectively at the apical membrane of the cells. In order to function as an anion exchanger, pendrin needs to be inserted at the plasma membrane (Taylor et al., 2002; RotmanPikielny et al., 2002). The precise mechanisms that regulate this process are still unknown. Muscella et al. (2008) studied the subcellular localization of pendrin in the rat thyroid PCCl3 cell line and demonstrated that translocation of pendrin from the cytosol to the plasma membrane occurs via a PKC-␧ dependent pathway following short-term exposure to insulin. Another study demonstrated that TSH rapidly upregulates pendrin protein insertion at the plasma membrane and leads to an increase in iodide efflux (Pesce and Kopp, 2007). This effect occurs within minutes and is mediated through the PKA pathway (Pesce and Kopp, 2007). The increase in pendrin abundance at the plasma membrane correlates with the phosphorylation of pendrin (Pesce and Kopp, 2007). However, further studies are necessary to determine whether phosphorylation is a prerequisite for membrane insertion of pendrin. Although TSH regulates apical iodide efflux, it does not stimulate the expression of SLC26A4 mRNA (Royaux et al., 2000). Similarly, insulin does not induce SLC26A4 expression (Royaux et al., 2000). However, TSH and insulin appear to enhance SLC26A4 gene expression in the presence of thyroglobulin (Suzuki and Kohn, 2006). Intriguingly, pendrin expression is significantly induced by thyroglobulin, the protein necessary for thyroid hormone synthesis stored in the colloidal space of thyrocytes (Royaux et al., 2000). In contrast, thyroglobulin suppresses expression of several thyroidspecific genes including TSHR, NIS, and TPO, TG, PAX8, TTF1, and TTF2 (Suzuki et al., 1998). It has been proposed that thyroglobulin, by mediating differential expression of these genes regulates the rate of iodide efflux into the follicular lumen and may thus play an important role in regulating thyroid function under constant levels of TSH (Suzuki and Kohn, 2006). 5. Mutations of pendrin To date, more than 150 mutations in the SLC26A4 gene have been reported in patients with Pendred syndrome (http://www.healthcare.uiowa.edu/laboratories/pendredandbor/ slcMutations.htm). The mutations are dispersed throughout the gene. The majority of the SLC26A4 mutations are missense mutations with a much smaller portion represented by nonsense, splice site, and frameshift mutations (Kopp, 1999b). Patients from consanguineous families are homozygous for mutations in the SLC26A4 gene, whereas compound heterozygous mutations of the gene are found in affected individuals of non-consanguineous

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families or in sporadic cases (Kopp, 2000). The prevalence of recurring mutations varies among different ethnic groups (Park et al., 2003). For instance, three specific mutations, L236P, T416P, IVS8 + 1G → A occur relatively frequently in European populations (Campbell et al., 2001). In Japanese patients, the H723R accounts for 53% of the mutant alleles (Park et al., 2003; Tsukamoto et al., 2003), and in Koreans, the H723R mutation accounts for 40% of patients with Pendred syndrome (Park et al., 2005). Only few studies have determined whether the mutant pendrin proteins retain their ability to transport iodide (Gillam et al., 2004, 2005; Taylor et al., 2002; Dossena et al., 2006; Scott et al., 2000). Scott et al. (2000) demonstrated that iodide transport activity was abolished in mutations found in patients with Pendred syndrome (L236P, T416P, E384G). Mutations that have been reported only in individuals with non-goitrous deafness associated with an EVA were able to mediate some transport of iodide, although to a lesser extent compared to the wild-type SLC26A4 (Scott et al., 2000). These observations led to the suggestion that absence of goiter in patients with familial EVA may be due to the residual activity of certain pendrin mutants (Scott et al., 2000). Subsequent studies of common mutations found in patients with Pendred syndrome and familial EVA have not confirmed this hypothesis (Tsukamoto et al., 2003; Taylor et al., 2002). Recently, Pera et al. (2008b) characterized a number of missense mutations found both in normal individuals and patients with Pendred syndrome and EVA. Four of the analyzed mutations, namely E29Q, V88I/R409H, G424D, and T485R showed a significant reduction in chloride/iodide transport, whereas P140H, Q413P, Q514K and D724G had an abolished transport activity, as demonstrated by a fluorometric method (Pera et al., 2008b). The majority of truncation mutations and the deletion or introduction of a charged amino acid or proline in the SLC26A4 protein sequence result in a substantial or total loss-of-function in term of anion transport (Pera et al., 2008b; Dossena et al., 2009). It has been shown that the loss of ability to transport iodide in some of these mutations is due to retention of the mutated proteins in the endoplasmic reticulum (Rotman-Pikielny et al., 2002). However, the exact mechanisms responsible for defects in protein processing and plasma membrane targeting of pendrin remain to be elucidated. A recent study by Yoon et al. (2008) has suggested that processing of pendrin mutant proteins involves different intracellular mechanisms that are specific for each mutant protein. The majority of the mutant pendrin proteins explored in this study were retained in various intracellular compartments including the ER and displayed an impaired chloride/bicarbonate exchange activity. Each of the studied mutants had a different cellular localization and displayed a different degree of N-glycosylation (Yoon et al., 2008).

6. The function of pendrin in the inner ear Several studies explored the expression and function of pendrin in the inner ear (Everett et al., 1999, 2001; Wangemann et al., 2004; Nakaya et al., 2007; Wangemann et al., 2007). In the developing inner ear of the mouse, SLC26A4 mRNA is expressed in discrete areas of the endolymphatic duct and sac, the utricle and saccule (Everett et al., 1999). These regions of the inner ear are important for maintaining the composition and resorption of endolymph, which is a prerequisite for normal function of the inner ear. The creation of a pendrin-knockout mouse has provided the tool for a better understanding of the role of pendrin in the inner ear and the mechanisms underlying deafness in Pendred syndrome (Everett et al., 2001). The Slc26A4 deficient mice are completely deaf and display a vestibular phenotype with head tilting, unsteady gait, circling, and an abnormal reaching response (Everett et al., 2001). Anatomically, the inner ear of these animals develops normally until embryonic day 15, after which a number of defects

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are observed, including dilatation of the endolymphatic duct and sac, degeneration of sensory cells, and malformation of otoconia and otoconial membranes (Everett et al., 2001). Further studies revealed that pendrin-knockout mice lack the endocochlear potential as a result of a loss of expression of the potassium channel Kcnj10 (Wangemann et al., 2004, 2007). Moreover, the loss of pendrin-mediated exchange of chloride with bicarbonate leads to acidification of the endolymph, which in turn results in the inactivation of two apical calcium channels (TRPV5 and TRPV6) (Nakaya et al., 2007). Inactivation of these channels regulating calcium absorption in the vestibular system leads to an increased calcium concentration in the endolymph (Nakaya et al., 2007). The scala media of Slc26a4−/− mice is enlarged and their cochlear development is delayed (Wangemann et al., 2009). Moreover, the expression of deiodinase type 2 and 3 (Dio2, Dio3), which control the levels of the active thyroid hormone triiodothyronine (T3), as well as of T3 regulated genes such as Tectorin B (Tectb) occurs later in development. Although the systemic levels of thyroid hormones are normal in Slc26a4−/− mice are normal, it has been suggested that these findings could indicate local hypothyroidism which could be causally involved in the delayed cochlear development (Wangemann et al., 2009). Mice with targeted disruption of the winged helix/forkhead gene Foxi1 lack pendrin expression in the inner ear and develop a phenotype that resembles the one found in the pendrin-knockout mouse model (Hulander et al., 2003). Foxi1−/− mice are deaf and have a dilated endolymphatic duct and sac. In addition, they also lack the endocochlear potential. These findings suggest that Foxi1 is a transcriptional regulator of pendrin and further support the role of pendrin in maintaining the composition and balance of the endolymph in the inner ear (Hulander et al., 2003).

7. The role of pendrin in the kidney In the kidney, pendrin is expressed in the cortical collecting duct (Soleimani et al., 2001; Royaux et al., 2001). In the cortical collecting duct pendrin is inserted into the apical membrane of the intercalated type B cells, and in intercalated type non-A-non-B cells (Soleimani et al., 2001; Royaux et al., 2001). Type B cells are known to secrete bicarbonate, while type A cells mediate hydrogen secretion (Wall, 2005). The physiological role of type non-A-non-B cells is currently unknown (Wall, 2005). Bicarbonate secretion increases during metabolic alkalosis and decreases in metabolic acidosis (Tsuruoka and Schwartz, 1996, 1999). Thus, it has been suggested that pendrin may have a role in exchanging anions in type B intercalated cells. First insights into the role of pendrin in the kidney revealed that pendrin is able to exchange chloride with bicarbonate, hydroxide, and formate in heterologous cells expressing pendrin (Scott and Karniski, 2000; Soleimani et al., 2001). The ability of pendrin to mediate secretion of bicarbonate has been demonstrated by a number of studies in vivo (Royaux et al., 2001). In mice, pendrin expression significantly increased during metabolic alkalosis, which correlates with the predominant localization of the protein at the apical membrane (Wagner et al., 2002). In contrast, under conditions of metabolic acidosis, pendrin expression is decreased and results in the translocation of pendrin from the apical membrane to cytosolic compartments. Another study demonstrated that renal tubules isolated from alkali-loaded wild-type mice show normal secretion of bicarbonate, whereas tubules from alkali-loaded pendrin-knockout mice are unable to secrete bicarbonate (Royaux et al., 2001). Collectively, these results suggest that pendrin is involved in bicarbonate secretion during metabolic alkalosis. Interestingly, both patients with Pendred syndrome and pendrin-knockout mice have a normal renal function and do not display abnormalities in acid–base

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metabolism or fluid and electrolyte homeostasis under basal conditions (Royaux et al., 2001; Verlander et al., 2003; Wall et al., 2004). This indicates that other chloride-base exchangers can compensate for the loss of pendrin. In addition to its ability to secrete bicarbonate, pendrin has also been implicated in renal chloride absorption. The level of pendrin expression is upregulated in response to treatment with the aldosterone analogue deoxycorticosterone pivalate (DOCP) and following dietary Cl− restriction (Verlander et al., 2003; Wall et al., 2004). Aldosterone increases vascular volume and blood pressure by stimulating renal sodium and chloride absorption. During sodium chloride restriction, which increases aldosterone levels, pendrin null mice have a lower blood pressure and display a more severe metabolic alkalosis compared to wild-type mice, most likely due to the decreased ability of the knockout mice to absorb chloride and secrete bicarbonate (Verlander et al., 2006). Pendrin has been demonstrated to mediate protein abundance and function of the epithelial sodium channel ENaC, located at the apical membrane of the principal cells in the kidney (Kim et al., 2007). In particular, during sodium chloride restriction, the function and protein abundance of ENaC is significantly reduced in pendrin-knockout mice (Kim et al., 2007). Altogether, these findings suggest that pendrin is involved in the regulation of electrolyte homeostasis and blood pressure by mediating net acid and chloride excretion (Verlander et al., 2003, 2006). Pendrin may thus represent a potential target for the treatment of hypertension (Verlander et al., 2003, 2006). 8. Pendrin in other tissues In addition to its expression in the thyroid, the inner ear, and the kidney, pendrin expression is also found in other tissues. Imunohistochemical analysis of placenta has demonstrated that NIS is expressed on the entire membrane of the cytotrophoblast, while pendrin is expressed at the brush border of syncytiotrophoblast cells facing the maternal side (Bidart et al., 2000). To date, the role of NIS and pendrin in the placenta remain to be determined. Iodide is an essential component of milk, where its concentration is much higher than in maternal plasma (Delange et al., 1986). The uptake of iodide into alveolar epithelial cells occurs through NIS, which is expressed in the basolateral membrane during lactation (Dohan et al., 2003). Studies using immunoblotting analysis have also confirmed that pendrin is expressed in the lactating mammary gland (Rillema and Hill, 2003). Treatment of lactating mouse mammary glands with insulin, cortisol and prolactin has been associated with a three-fold increase of pendrin protein expression (Rillema and Hill, 2003). However, the subcellular distribution and physiological importance of pendrin in the lactating mammary gland is still unknown. Very low levels of SLC26A4 mRNA expression have been reported in the lung, prostate, endometrium, and the testis, specifically in Sertoli cells (Lacroix et al., 2004; Pedemonte et al., 2007). In the lung, pendrin expression increases after treatment with IL-4 and it has been proposed to be involved in the transport of thiocyanate (Pedemonte et al., 2007). 9. Conclusions and perspective Many questions surrounding the physiological role of pendrin are incompletely solved. As discussed, iodide can reach the follicular lumen independent of pendrin. This suggests the presence of other iodide channels in thyrocytes, but their identity remains unclear. Alternatively, iodide may reach the follicular lumen through chloride channels. The subcellular distribution of pendrin by TSH awaits further characterization. While it is apparent that pendrin has an interesting role in the kidney, and may perhaps

be a target for the therapy of hypertension, its functional role in the pathogenesis of salt-mediated hypertension needs more research and the current data are limited to studies in mice. While there is an increasing, but still incomplete understanding of the functional significance of pendrin in the inner ear, its potential physiological role in tissues such as the lung, placenta, and the lactating breast is currently unknown.

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