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Shin-ichi Usami - One of the best experts on this subject based on the ideXlab platform.
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mutation spectrum and genotype phenotype correlation of hearing loss patients caused by slc26a4 mutations in the japanese a large cohort study
Journal of Human Genetics, 2014Co-Authors: Maiko Miyagawa, Shinya Nishio, Shin-ichi UsamiAbstract:Mutations in SLC26A4 cause a broad phenotypic spectrum, from typical Pendred Syndrome to nonsyndromic hearing loss associated with enlarged vestibular aqueduct. Identification of these mutations is important for accurate diagnosis, proper medical management and appropriate genetic counseling and requires updated information regarding spectrum, clinical characteristics and genotype–phenotype correlations, based on a large cohort. In 100 patients with bilateral enlarged vestibular aqueduct among 1511 Japanese hearing loss probands registered in our gene bank, goiter data were available for 79, of whom 15 had Pendred Syndrome and 64 had nonsyndromic hearing loss. We clarified the mutation spectrum for the SLC26A4 mutations and also summarized hearing levels, progression, fluctuation and existence of genotype–phenotype correlation. SLC26A4 mutations were identified in 82 of the 100 patients (82.0%). Of the Pendred Syndrome patients, 93% (14/15) were carriers, as were 77% (49/64) of the nonsyndromic hearing loss patients. Clinical characteristics of patients with SLC26A4 mutations were congenital, fluctuating and progressive hearing loss usually associated with vertigo and/or goiter. We found no genotype–phenotype correlations, indicating that, unlike in the case of GJB2 mutations, the phenotype cannot be predicted from the genotype. Our mutation analysis confirmed the importance of mutations in the SLC26A4 gene among hearing loss patients with enlarged vestibular aqueduct and revealed the mutation spectrum, essential information when performing genetic testing.
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pathogenic substitution of ivs15 5g a in slc26a4 in patients of okinawa islands with enlarged vestibular aqueduct Syndrome or Pendred Syndrome
BMC Medical Genetics, 2013Co-Authors: Akira Ganaha, Shin-ichi Usami, Tadashi Kaname, Kumiko Yanagi, Kenji Naritomi, Tetsuya Tono, Mikio SuzukiAbstract:Pendred Syndrome (PS) and nonsyndromic hearing loss associated with enlarged vestibular aqueduct (EVA) are caused by SLC26A4 mutations. The Okinawa Islands are the southwestern-most islands of the Japanese archipelago. And ancestral differences have been reported between people from Okinawa Island and those from the main islands of Japan. To confirm the ethnic variation of the spectrum of SLC26A4 mutations, we investigated the frequencies of SLC26A4 mutations and clinical manifestations of patients with EVA or PS living in the Okinawa Islands. We examined 22 patients with EVA or PS from 21 unrelated families in Okinawa Islands. The patient’s clinical history, findings of physical and otoscopic examinations, hearing test, and computed tomography (CT) scan of the temporal bones were recorded. To detect mutations, all 21 exons and the exon–intron junctions of SLC26A4 were sequenced for all subjects. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) for SLC26A4 and calculations using the comparative CT (2−ΔΔCT) method were used to determine the pathogenicity associated with gene substitutions. SLC26A4 mutations were identified in 21 of the 22 patients. We found a compound heterozygous mutation for IVS15 + 5G > A/H723R in nine patients (41%), a homozygous substitution of IVS15 + 5G > A in six patients (27%), and homozygous mutation for H723R in five patients (23%). The most prevalent types of SLC26A4 alleles were IVS15 + 5G > A and H723R, which both accounted for 15/22 (68%) of the patients. There were no significant correlations between the types of SLC26A4 mutation and clinical manifestations. Based on qRT-PCR results, expression of SLC26A4 was not identified in patients with the homozygous substitution of IVS15 + 5G > A. The substitution of IVS15 + 5G > A in SLC26A4 was the most common mutation in uniquely found in patients with PS and EVA in Okinawa Islands. This suggested that the spectrum of SLC26A4 mutation differed from main islands of Japan and other East Asian countries. The substitution of IVS15 + 5G > A leads to a loss of SLC26A expression and results in a phenotype of PS and EVA.
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salicylate restores transport function and anion exchanger activity of missense pendrin mutations
Hearing Research, 2010Co-Authors: Kenji Ishihara, Shin-ichi Usami, Shuhei Okuyama, Shun Kumano, Koji Iida, Hiroshi Hamana, Michio Murakoshi, Toshimitsu Kobayashi, Katsuhisa Ikeda, Yoichi HagaAbstract:The SLC26A4 gene encodes the transmembrane protein pendrin, which is involved in the homeostasis of the ion concentration of the endolymph of the inner ear, most likely by acting as a chloride/bicarbonate transporter. Mutations in the SLC26A4 gene cause sensorineuronal hearing loss. However, the mechanisms responsible for such loss have remained unknown. Therefore, in this study, we focused on the function of ten missense pendrin mutations (p.P123S (Pendred Syndrome), p.M147V (NSEVA), p.K369E (NSEVA), p.A372V (Pendred Syndrome/NSEVA), p.N392Y (Pendred Syndrome), p.C565Y (NSEVA), p.S657N (NSEVA), p.S666F (NSEVA), p.T721M (NSEVA) and p.H723R (Pendred Syndrome/NSEVA)) reported in Japanese patients, and analyzed their cellular localization and anion exchanger activity using HEK293 cells transfected with each mutant gene. Immunofluorescent staining of the cellular localization of the pendrin mutants revealed that p.K369E and p.C565Y, as well as wild-type pendrin, were transported to the plasma membrane, while 8 other mutants were retained in the cytoplasm. Furthermore, we analyzed whether salicylate, as a pharmacological chaperone, restores normal plasma membrane localization of 8 pendrin mutants retained in the cytoplasm to the plasma membrane. Incubation with 10 mM of salicylate of the cells transfected with the mutants induced the transport of 4 pendrin mutants (p.P123S, p.M147V, p.S657Y and p.H723R) from the cytoplasm to the plasma membrane and restored the anion exchanger activity. These findings suggest that salicylate might contribute to development of a new method of medical treatment for sensorineuronal hearing loss caused by the mutation of the deafness-related proteins, including pendrin.
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Distribution and frequencies of PDS (SLC26A4) mutations in Pendred Syndrome and nonsyndromic hearing loss associated with enlarged vestibular aqueduct: a unique spectrum of mutations in Japanese
European Journal of Human Genetics, 2003Co-Authors: Koji Tsukamoto, Satoko Abe, Hiroaki Suzuki, Daisuke Harada, Atsushi Namba, Shin-ichi UsamiAbstract:Molecular diagnosis makes a substantial contribution to precise diagnosis, subclassification, prognosis, and selection of therapy. Mutations in the PDS (SLC26A4) gene are known to be responsible for both Pendred Syndrome and nonsyndromic hearing loss associated with enlarged vestibular aqueduct, and the molecular confirmation of the PDS gene has become important in the diagnosis of these conditions. In the present study, PDS mutation analysis confirmed that PDS mutations were present and significantly responsible in 90% of Pendred families, and in 78.1% of families with nonsyndromic hearing loss associated with enlarged vestibular aqueduct. Furthermore, variable phenotypic expression by the same combination of mutations indicated that these two conditions are part of a continuous category of disease. Interestingly, the PDS mutation spectrum in Japanese, including the seven novel mutations revealed by this study, is very different from that found in Caucasians. Of the novel mutations detected, 53% were the H723R mutation, suggesting a possible founder effect. Ethnic background is therefore presumably important and should be noted when genetic testing is being performed. The PDS gene mutation spectrum in Japanese may be representative of those in Eastern Asian populations and its elucidation is expected to facilitate the molecular diagnosis of a variety of diseases.
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Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations
Human Genetics, 1999Co-Authors: Shin-ichi Usami, Satoko Abe, Michael D. Weston, Hideichi Shinkawa, Guy Van Camp, William J. KimberlingAbstract:Enlarged vestibular aqueduct (EVA), known as the most common form of inner ear abnormality, has recently been of particular genetic interest because this anomaly is inherited in a recessive manner. The locus for non-syndromic sensorineural hearing loss with EVA has been mapped to the same chromosomal region, 7q31, as the Pendred Syndrome locus. In the present study, seven mutations in the PDS gene (PDS), the gene responsible for Pendred Syndrome, have been found in families of non-syndromic sensorineural hearing loss with EVA. One family is homozygous, three families are compound heterozygotes, and two families are heterozygous but with no other mutation detected. The present results provide evidence that mutations in PDS cause both syndromic and non-syndromic hearing loss.
Chuan-jen Hsu - One of the best experts on this subject based on the ideXlab platform.
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targeted next generation sequencing facilitates genetic diagnosis and provides novel pathogenetic insights into deafness with enlarged vestibular aqueduct
The Journal of Molecular Diagnostics, 2019Co-Authors: Yinhung Lin, Chuan-jen Hsu, Yihsin Lin, Chihshan Chen, Tienchen Liu, Peilung ChenAbstract:Enlarged vestibular aqueduct (EVA) is an inner-ear malformation associated with sensorineural hearing impairment. Most EVAs are associated with Pendred Syndrome and nonsyndromic autosomal recessive deafness–4 (DFNB4), two autosomal-recessive disorders caused by mutations in SLC26A4. However, many EVA patients cannot have a confirmed diagnosis by screening common SLC26A4 mutations, constituting an enigma in genetic diagnosis. To enable comprehensive genetic examination and explore the etiologies of EVA, we designed a next-generation sequencing panel targeting the entire length of 3 Pendred Syndrome/DFNB4 genes (SLC26A4, FOXI1, and KCNJ10) and exons of 10 other genes related to EVA and performed genetic testing in 50 EVA families without confirmative results on screening for SLC26A4 hotspots (c.919-2A>G and p.H723R). Bi-allelic SLC26A4 mutations were identified in 34 families and EYA1 mutations in two families, yielding a diagnostic rate of 72% (36 of 50). In addition, two variants were identified in KCNJ10 and FOXI1, but findings did not support the previous hypothesis that mutations in these two genes are probable contributors to EVA through recessive inheritance or digenic inheritance with SLC26A4. Of note, a large SLC26A4 deletion was confirmed in one step using our panel. These results show the utility of a next-generation sequencing–based panel to address EVA families by identifying various types of gene mutations with satisfactory diagnostic yields and provide novel insights into the pathogenesis of EVA.
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Phenotypic Analyses and Mutation Screening of the SLC26A4 and FOXI1 Genes in 101 Taiwanese Families with Bilateral Nonsyndromic Enlarged Vestibular Aqueduct (DFNB4) or Pendred Syndrome
Audiology and Neurotology, 2009Co-Authors: Peijer Chen, Po-lin Yeh, Wuh-liang Hwu, Chuan-jen HsuAbstract:Recessive mutations in the SLC26A4 gene are responsible for nonsyndromic enlarged vestibular aqueduct (EVA) and Pendred Syndrome. However, in some affected families, only 1 or 0 mut
Philine Wangemann - One of the best experts on this subject based on the ideXlab platform.
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free radical stress mediated loss of kcnj10 protein expression in stria vascularis contributes to deafness in Pendred Syndrome mouse model
American Journal of Physiology-renal Physiology, 2008Co-Authors: Ruchira Singh, Philine WangemannAbstract:Pendred Syndrome is due to loss-of-function mutations of Slc26a4, which codes for the HCO3− transporter pendrin. Loss of pendrin causes deafness via a loss of the K+ channel Kcnj10 in stria vascula...
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loss of cochlear hco3 secretion causes deafness via endolymphatic acidification and inhibition of ca2 reabsorption in a Pendred Syndrome mouse model
American Journal of Physiology-renal Physiology, 2007Co-Authors: Philine Wangemann, Rajanikanth J Maganti, Kazuhiro Nakaya, Erin M Itza, Joel D Sanneman, Donald G Harbidge, Sara E Billings, Daniel C MarcusAbstract:Pendred Syndrome, characterized by childhood deafness and postpuberty goiter, is caused by mutations of SLC26A4, which codes for the anion exchanger pendrin. The goal of the present study was to de...
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macrophage invasion contributes to degeneration of stria vascularis in Pendred Syndrome mouse model
BMC Medicine, 2006Co-Authors: Sairam V Jabba, Lorraine A Everett, Ruchira Singh, Susan M Wall, Alisha Oelke, Rajanikanth J Maganti, Sherry D Fleming, Eric D Green, Philine WangemannAbstract:Background Pendred Syndrome, an autosomal-recessive disorder characterized by deafness and goiter, is caused by a mutation of SLC26A4, which codes for the anion exchanger pendrin. We investigated the relationship between pendrin expression and deafness using mice that have (Slc26a4+/+ or Slc26a4+/-) or lack (Slc26a4-/-) a complete Slc26a4 gene. Previously, we reported that stria vascularis of adult Slc26a4-/- mice is hyperpigmented and that marginal cells appear disorganized. Here we determine the time course of hyperpigmentation and marginal cell disorganization, and test the hypothesis that inflammation contributes to this tissue degeneration.
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Macrophage invasion contributes to degeneration of stria vascularis in Pendred Syndrome mouse model
BMC Medicine, 2006Co-Authors: Sairam V Jabba, Lorraine A Everett, Ruchira Singh, Susan M Wall, Alisha Oelke, Rajanikanth J Maganti, Eric D Green, Sherry Fleming, Philine WangemannAbstract:Background Pendred Syndrome, an autosomal-recessive disorder characterized by deafness and goiter, is caused by a mutation of SLC26A4 , which codes for the anion exchanger pendrin. We investigated the relationship between pendrin expression and deafness using mice that have ( Slc26a4 ^+/+ or Slc26a4 ^+/-) or lack ( Slc26a4 ^-/-) a complete Slc26a4 gene. Previously, we reported that stria vascularis of adult Slc26a4 ^-/- mice is hyperpigmented and that marginal cells appear disorganized. Here we determine the time course of hyperpigmentation and marginal cell disorganization, and test the hypothesis that inflammation contributes to this tissue degeneration. Methods Slc26a4 ^-/- and age-matched control ( Slc26a4 ^+/+ or Slc26a4 ^+/-) mice were studied at four postnatal (P) developmental stages: before and after the age that marks the onset of hearing (P10 and P15, respectively), after weaning (P28-41) and adult (P74-170). Degeneration and hyperpigmentation stria vascularis was evaluated by confocal microscopy. Gene expression in stria vascularis was analyzed by microarray and quantitative RT-PCR. In addition, the expression of a select group of genes was quantified in spiral ligament, spleen and liver to evaluate whether expression changes seen in stria vascularis are specific for stria vascularis or systemic in nature. Results Degeneration of stria vascularis defined as hyperpigmentation and marginal cells disorganization was not seen at P10 or P15, but occurred after weaning and was associated with staining for CD68 , a marker for macrophages. Marginal cells in Slc26a4 ^-/-, however, had a larger apical surface area at P10 and P15. No difference in the expression of Lyzs , C3 and Cd45 was found in stria vascularis of P15 Slc26a4 ^+/- and Slc26a4 ^-/- mice. However, differences in expression were found after weaning and in adult mice. No difference in the expression of markers for acute inflammation, including Il1a , Il6 , Il12a , Nos2 and Nos3 were found at P15, after weaning or in adults. The expression of macrophage markers including Ptprc (= Cd45 ), Cd68 , Cd83 , Lyzs , Lgals3 (= Mac2 antigen), Msr2 , Cathepsins B, S, and K ( Ctsb, Ctss, Ctsk ) and complement components C1r , C3 and C4 was significantly increased in stria vascularis of adult Slc26a4 ^-/- mice compared to Slc26a4 ^+/+ mice. Expression of macrophage markers Cd45 and Cd84 and complement components C1r and C3 was increased in stria vascularis but not in spiral ligament, liver or spleen of Slc26a4 ^-/- compared to Slc26a4 ^+/- mice. The expression of Lyzs was increased in stria vascularis and spiral ligament but not in liver or spleen. Conclusion The data demonstrate that hyperpigmentation of stria vascularis and marginal cell reorganization in Slc26a4 ^-/- mice occur after weaning, coinciding with an invasion of macrophages. The data suggest that macrophage invasion contributes to tissue degeneration in stria vascularis, and that macrophage invasion is restricted to stria vascularis and is not systemic in nature. The delayed onset of degeneration of stria vascularis suggests that a window of opportunity exists to restore/preserve hearing in mice and therefore possibly in humans suffering from Pendred Syndrome.
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BMC Medicine BioMed Central
2006Co-Authors: Sairam V Jabba, Lorraine A Everett, Ruchira Singh, Susan M Wall, Alisha Oelke, Rajanikanth J Maganti, Eric D Green, Sherry Fleming, Philine WangemannAbstract:Research article Macrophage invasion contributes to degeneration of stria vascularis in Pendred Syndrome mouse mode
Lorraine A Everett - One of the best experts on this subject based on the ideXlab platform.
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macrophage invasion contributes to degeneration of stria vascularis in Pendred Syndrome mouse model
BMC Medicine, 2006Co-Authors: Sairam V Jabba, Lorraine A Everett, Ruchira Singh, Susan M Wall, Alisha Oelke, Rajanikanth J Maganti, Sherry D Fleming, Eric D Green, Philine WangemannAbstract:Background Pendred Syndrome, an autosomal-recessive disorder characterized by deafness and goiter, is caused by a mutation of SLC26A4, which codes for the anion exchanger pendrin. We investigated the relationship between pendrin expression and deafness using mice that have (Slc26a4+/+ or Slc26a4+/-) or lack (Slc26a4-/-) a complete Slc26a4 gene. Previously, we reported that stria vascularis of adult Slc26a4-/- mice is hyperpigmented and that marginal cells appear disorganized. Here we determine the time course of hyperpigmentation and marginal cell disorganization, and test the hypothesis that inflammation contributes to this tissue degeneration.
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Macrophage invasion contributes to degeneration of stria vascularis in Pendred Syndrome mouse model
BMC Medicine, 2006Co-Authors: Sairam V Jabba, Lorraine A Everett, Ruchira Singh, Susan M Wall, Alisha Oelke, Rajanikanth J Maganti, Eric D Green, Sherry Fleming, Philine WangemannAbstract:Background Pendred Syndrome, an autosomal-recessive disorder characterized by deafness and goiter, is caused by a mutation of SLC26A4 , which codes for the anion exchanger pendrin. We investigated the relationship between pendrin expression and deafness using mice that have ( Slc26a4 ^+/+ or Slc26a4 ^+/-) or lack ( Slc26a4 ^-/-) a complete Slc26a4 gene. Previously, we reported that stria vascularis of adult Slc26a4 ^-/- mice is hyperpigmented and that marginal cells appear disorganized. Here we determine the time course of hyperpigmentation and marginal cell disorganization, and test the hypothesis that inflammation contributes to this tissue degeneration. Methods Slc26a4 ^-/- and age-matched control ( Slc26a4 ^+/+ or Slc26a4 ^+/-) mice were studied at four postnatal (P) developmental stages: before and after the age that marks the onset of hearing (P10 and P15, respectively), after weaning (P28-41) and adult (P74-170). Degeneration and hyperpigmentation stria vascularis was evaluated by confocal microscopy. Gene expression in stria vascularis was analyzed by microarray and quantitative RT-PCR. In addition, the expression of a select group of genes was quantified in spiral ligament, spleen and liver to evaluate whether expression changes seen in stria vascularis are specific for stria vascularis or systemic in nature. Results Degeneration of stria vascularis defined as hyperpigmentation and marginal cells disorganization was not seen at P10 or P15, but occurred after weaning and was associated with staining for CD68 , a marker for macrophages. Marginal cells in Slc26a4 ^-/-, however, had a larger apical surface area at P10 and P15. No difference in the expression of Lyzs , C3 and Cd45 was found in stria vascularis of P15 Slc26a4 ^+/- and Slc26a4 ^-/- mice. However, differences in expression were found after weaning and in adult mice. No difference in the expression of markers for acute inflammation, including Il1a , Il6 , Il12a , Nos2 and Nos3 were found at P15, after weaning or in adults. The expression of macrophage markers including Ptprc (= Cd45 ), Cd68 , Cd83 , Lyzs , Lgals3 (= Mac2 antigen), Msr2 , Cathepsins B, S, and K ( Ctsb, Ctss, Ctsk ) and complement components C1r , C3 and C4 was significantly increased in stria vascularis of adult Slc26a4 ^-/- mice compared to Slc26a4 ^+/+ mice. Expression of macrophage markers Cd45 and Cd84 and complement components C1r and C3 was increased in stria vascularis but not in spiral ligament, liver or spleen of Slc26a4 ^-/- compared to Slc26a4 ^+/- mice. The expression of Lyzs was increased in stria vascularis and spiral ligament but not in liver or spleen. Conclusion The data demonstrate that hyperpigmentation of stria vascularis and marginal cell reorganization in Slc26a4 ^-/- mice occur after weaning, coinciding with an invasion of macrophages. The data suggest that macrophage invasion contributes to tissue degeneration in stria vascularis, and that macrophage invasion is restricted to stria vascularis and is not systemic in nature. The delayed onset of degeneration of stria vascularis suggests that a window of opportunity exists to restore/preserve hearing in mice and therefore possibly in humans suffering from Pendred Syndrome.
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BMC Medicine BioMed Central
2006Co-Authors: Sairam V Jabba, Lorraine A Everett, Ruchira Singh, Susan M Wall, Alisha Oelke, Rajanikanth J Maganti, Eric D Green, Sherry Fleming, Philine WangemannAbstract:Research article Macrophage invasion contributes to degeneration of stria vascularis in Pendred Syndrome mouse mode
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pendrin encoded by the Pendred Syndrome gene resides in the apical region of renal intercalated cells and mediates bicarbonate secretion
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Ines E. Royaux, Lorraine A Everett, Susan M Wall, Lawrence P Karniski, Koichi Suzuki, Mark A Knepper, Eric D GreenAbstract:Pendrin is an anion transporter encoded by the PDS/Pds gene. In humans, mutations in PDS cause the genetic disorder Pendred Syndrome, which is associated with deafness and goiter. Previous studies have shown that this gene has a relatively restricted pattern of expression, with PDS/Pds mRNA detected only in the thyroid, inner ear, and kidney. The present study examined the distribution and function of pendrin in the mammalian kidney. Immunolocalization studies were performed using anti-pendrin polyclonal and monoclonal antibodies. Labeling was detected on the apical surface of a subpopulation of cells within the cortical collecting ducts (CCDs) that also express the H+-ATPase but not aquaporin-2, indicating that pendrin is present in intercalated cells of the CCD. Furthermore, pendrin was detected exclusively within the subpopulation of intercalated cells that express the H+-ATPase but not the anion exchanger 1 (AE1) and that are thought to mediate bicarbonate secretion. The same distribution of pendrin was observed in mouse, rat, and human kidney. However, pendrin was not detected in kidneys from a Pds-knockout mouse. Perfused CCD tubules isolated from alkali-loaded wild-type mice secreted bicarbonate, whereas tubules from alkali-loaded Pds-knockout mice failed to secrete bicarbonate. Together, these studies indicate that pendrin is an apical anion transporter in intercalated cells of CCDs and has an essential role in renal bicarbonate secretion.
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targeted disruption of mouse pds provides insight about the inner ear defects encountered in Pendred Syndrome
Human Molecular Genetics, 2001Co-Authors: Lorraine A Everett, Inna A Belyantseva, Konrad Nobentrauth, Raquel Cantos, Amy Chen, Sneha I Thakkar, Shelley Hoogstratenmiller, Bechara Kachar, Eric D GreenAbstract:Following the positional cloning of PDS, the gene mutated in the deafness/goitre disorder Pendred Syndrome (PS), numerous studies have focused on defining the role of PDS in deafness and PS as well as elucidating the function of the PDS-encoded protein (pendrin). To facilitate these efforts and to provide a system for more detailed study of the inner-ear defects that occur in the absence of pendrin, we have generated a Pds-knockout mouse. Pds(-/-) mice are completely deaf and also display signs of vestibular dysfunction. The inner ears of these mice appear to develop normally until embryonic day 15, after which time severe endolymphatic dilatation occurs, reminiscent of that seen radiologically in deaf individuals with PDS mutations. Additionally, in the second postnatal week, severe degeneration of sensory cells and malformation of otoconia and otoconial membranes occur, as revealed by scanning electron and fluorescence confocal microscopy. The ultrastructural defects seen in the Pds(-/-) mice provide important clues about the mechanisms responsible for the inner-ear pathology associated with PDS mutations.
Eric D Green - One of the best experts on this subject based on the ideXlab platform.
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macrophage invasion contributes to degeneration of stria vascularis in Pendred Syndrome mouse model
BMC Medicine, 2006Co-Authors: Sairam V Jabba, Lorraine A Everett, Ruchira Singh, Susan M Wall, Alisha Oelke, Rajanikanth J Maganti, Sherry D Fleming, Eric D Green, Philine WangemannAbstract:Background Pendred Syndrome, an autosomal-recessive disorder characterized by deafness and goiter, is caused by a mutation of SLC26A4, which codes for the anion exchanger pendrin. We investigated the relationship between pendrin expression and deafness using mice that have (Slc26a4+/+ or Slc26a4+/-) or lack (Slc26a4-/-) a complete Slc26a4 gene. Previously, we reported that stria vascularis of adult Slc26a4-/- mice is hyperpigmented and that marginal cells appear disorganized. Here we determine the time course of hyperpigmentation and marginal cell disorganization, and test the hypothesis that inflammation contributes to this tissue degeneration.
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Macrophage invasion contributes to degeneration of stria vascularis in Pendred Syndrome mouse model
BMC Medicine, 2006Co-Authors: Sairam V Jabba, Lorraine A Everett, Ruchira Singh, Susan M Wall, Alisha Oelke, Rajanikanth J Maganti, Eric D Green, Sherry Fleming, Philine WangemannAbstract:Background Pendred Syndrome, an autosomal-recessive disorder characterized by deafness and goiter, is caused by a mutation of SLC26A4 , which codes for the anion exchanger pendrin. We investigated the relationship between pendrin expression and deafness using mice that have ( Slc26a4 ^+/+ or Slc26a4 ^+/-) or lack ( Slc26a4 ^-/-) a complete Slc26a4 gene. Previously, we reported that stria vascularis of adult Slc26a4 ^-/- mice is hyperpigmented and that marginal cells appear disorganized. Here we determine the time course of hyperpigmentation and marginal cell disorganization, and test the hypothesis that inflammation contributes to this tissue degeneration. Methods Slc26a4 ^-/- and age-matched control ( Slc26a4 ^+/+ or Slc26a4 ^+/-) mice were studied at four postnatal (P) developmental stages: before and after the age that marks the onset of hearing (P10 and P15, respectively), after weaning (P28-41) and adult (P74-170). Degeneration and hyperpigmentation stria vascularis was evaluated by confocal microscopy. Gene expression in stria vascularis was analyzed by microarray and quantitative RT-PCR. In addition, the expression of a select group of genes was quantified in spiral ligament, spleen and liver to evaluate whether expression changes seen in stria vascularis are specific for stria vascularis or systemic in nature. Results Degeneration of stria vascularis defined as hyperpigmentation and marginal cells disorganization was not seen at P10 or P15, but occurred after weaning and was associated with staining for CD68 , a marker for macrophages. Marginal cells in Slc26a4 ^-/-, however, had a larger apical surface area at P10 and P15. No difference in the expression of Lyzs , C3 and Cd45 was found in stria vascularis of P15 Slc26a4 ^+/- and Slc26a4 ^-/- mice. However, differences in expression were found after weaning and in adult mice. No difference in the expression of markers for acute inflammation, including Il1a , Il6 , Il12a , Nos2 and Nos3 were found at P15, after weaning or in adults. The expression of macrophage markers including Ptprc (= Cd45 ), Cd68 , Cd83 , Lyzs , Lgals3 (= Mac2 antigen), Msr2 , Cathepsins B, S, and K ( Ctsb, Ctss, Ctsk ) and complement components C1r , C3 and C4 was significantly increased in stria vascularis of adult Slc26a4 ^-/- mice compared to Slc26a4 ^+/+ mice. Expression of macrophage markers Cd45 and Cd84 and complement components C1r and C3 was increased in stria vascularis but not in spiral ligament, liver or spleen of Slc26a4 ^-/- compared to Slc26a4 ^+/- mice. The expression of Lyzs was increased in stria vascularis and spiral ligament but not in liver or spleen. Conclusion The data demonstrate that hyperpigmentation of stria vascularis and marginal cell reorganization in Slc26a4 ^-/- mice occur after weaning, coinciding with an invasion of macrophages. The data suggest that macrophage invasion contributes to tissue degeneration in stria vascularis, and that macrophage invasion is restricted to stria vascularis and is not systemic in nature. The delayed onset of degeneration of stria vascularis suggests that a window of opportunity exists to restore/preserve hearing in mice and therefore possibly in humans suffering from Pendred Syndrome.
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BMC Medicine BioMed Central
2006Co-Authors: Sairam V Jabba, Lorraine A Everett, Ruchira Singh, Susan M Wall, Alisha Oelke, Rajanikanth J Maganti, Eric D Green, Sherry Fleming, Philine WangemannAbstract:Research article Macrophage invasion contributes to degeneration of stria vascularis in Pendred Syndrome mouse mode
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Retention of pendrin in the endoplasmic reticulum is a major mechanism for Pendred Syndrome
2002Co-Authors: Pnina Rotman-pikielny, Eric D Green, Leonard D. Kohn, Koret Hirschberg, Padma Maruvada, Koichi Suzuki, Ines E. Royaux, Paul M. YenAbstract:Pendred Syndrome is a major cause of congenital deafness, goiter and defective iodide organification. Mutations in the transmembrane protein, pendrin, cause diminished export of iodide from thyroid follicular cells to the colloid and are associated with the Syndrome. We used green fluorescent protein (GFP) chimeras of wild-type (WT) pendrin and three common natural mutants (L236P, T416P and G384) to study their intracellular trafficking in living cells. Time-lapse imaging, dual color labeling and fluorescent recovery after photobleaching (FRAP) studies demonstrated that GFP–WT pendrin targets to the plasma membrane. In contrast, all three mutant pendrins were retained in the endoplasmic reticulum (ER) in co-localization studies with ER and Golgi markers. The ER retention of L236P appeared to be selective as this mutant did not prevent a viral membrane protein, VSVGtsO45 or wild-type pendrin from targeting the plasma membrane. These findings suggest that ER retention and defective plasma membrane targeting of pendrin mutants play a key role in the pathogenesis of Pendred Syndrome
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pendrin encoded by the Pendred Syndrome gene resides in the apical region of renal intercalated cells and mediates bicarbonate secretion
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Ines E. Royaux, Lorraine A Everett, Susan M Wall, Lawrence P Karniski, Koichi Suzuki, Mark A Knepper, Eric D GreenAbstract:Pendrin is an anion transporter encoded by the PDS/Pds gene. In humans, mutations in PDS cause the genetic disorder Pendred Syndrome, which is associated with deafness and goiter. Previous studies have shown that this gene has a relatively restricted pattern of expression, with PDS/Pds mRNA detected only in the thyroid, inner ear, and kidney. The present study examined the distribution and function of pendrin in the mammalian kidney. Immunolocalization studies were performed using anti-pendrin polyclonal and monoclonal antibodies. Labeling was detected on the apical surface of a subpopulation of cells within the cortical collecting ducts (CCDs) that also express the H+-ATPase but not aquaporin-2, indicating that pendrin is present in intercalated cells of the CCD. Furthermore, pendrin was detected exclusively within the subpopulation of intercalated cells that express the H+-ATPase but not the anion exchanger 1 (AE1) and that are thought to mediate bicarbonate secretion. The same distribution of pendrin was observed in mouse, rat, and human kidney. However, pendrin was not detected in kidneys from a Pds-knockout mouse. Perfused CCD tubules isolated from alkali-loaded wild-type mice secreted bicarbonate, whereas tubules from alkali-loaded Pds-knockout mice failed to secrete bicarbonate. Together, these studies indicate that pendrin is an apical anion transporter in intercalated cells of CCDs and has an essential role in renal bicarbonate secretion.