Identification of the Finnish founder mutation for diastrophic dysplasia (DTD)

Hästbacka, Johanna; Kerrebrock, Anne W.; Mokkala, K; Clines, G.; Lovett, Michael; Kaitila, Ilkka; A, de la Chapelle; Es, Lander

doi:10.1038/sj.ejhg.5200361

Cited by 55 publications

(73 citation statements)

References 21 publications

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“…(5,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). Mouse studies have revealed additional roles for these Slc26 proteins in mammalian physiology: deafness, goiter, and acidosis (Slc26a4, pendrin) (42-44), cochlear motor protein (Slc26a5, prestin) (45)(46)(47), proximal tubule NaCl absorption, nephrolithiasis, and intestinal HCO 3 Ϫ secretion (Slc26a6, Pat-1, CFEX) (8, 48 -52), sperm motility (Slc26a8, Tat-1) (53), and gastric acid secretion (Slc26a9) (14).…”

Section: Discussionmentioning

confidence: 99%

Slc26a9 Is Inhibited by the R-region of the Cystic Fibrosis Transmembrane Conductance Regulator via the STAS Domain

Chang

Plata

Sinđić

et al. 2009

Journal of Biological Chemistry

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SLC26 proteins function as anion exchangers, channels, and sensors. Previous cellular studies have shown that Slc26a3 and Slc26a6 interact with the R-region of the cystic fibrosis transmembrane conductance regulator (CFTR), (R)CFTR, via theSlc26 genes and proteins have attracted the attention of physiologists and geneticists. Why? Slc26a1 (Sat-1) was characterized as a Na ϩ -independent SO 4 2Ϫ transporter (1). Given the transport characteristics of the founding member of the gene family, Slc26 proteins were assumed to be sulfate transporters. Disease phenotypes, clone characterization, and family additions demonstrate that the Slc26 proteins are anion transporters or channels (2-4). These proteins have varied tissue expression patterns. At one extreme, Slc26a5 in mammals is found in the hair cells of the inner ear (5), whereas Slc26a2 (DTDST) is virtually ubiquitous in epithelial tissues (2).Several Slc26 proteins are found in the epithelia of the lung, intestine, stomach, pancreas, and kidney, usually in apical membranes. Interestingly these are also tissues and membranes in which the cystic fibrosis transmembrane conductance regulator (CFTR) 5 has been found functionally or by immunohistochemistry. Ko and co-workers (6 -8) examined the distribution of Slc26a3 and Slc26a6 in HCO 3 Ϫ secretory epithelia, and asked if an interaction might occur between these Slc26 proteins and CFTR. In particular, these studies indicate that in expression systems, there is a reciprocal-stimulatory interaction of the STAS (sulfate transporter anti-sigma) domains of Slc26a3 and Slc26a6 with the regulatory region (R-region) of CFTR. These investigators hypothesized that this stimulatory interaction could account for the differences in pancreatic insufficiency and sufficiency observed in cystic fibrosis patients. Nevertheless, knock-out Slc26a6 mouse studies reveal more complicated cell and tissue physiology (see "Discussion").Slc26a9 has been reported to be a Cl Ϫ -HCO 3 Ϫ exchanger (9, 10) or a large Cl Ϫ conductance (3,11,12). Loriol and co-workers (12) indicated that SLC26A9 has a Cl Ϫ conductance that may be stimulated by HCO 3 Ϫ . Two other groups have indicated that the Cl Ϫ conductance is not affected by the presence of HCO 3 Ϫ (10, 11). We have recently demonstrated that Slc26a9 functions as both an electrogenic nCl Ϫ -HCO 3 Ϫ exchanger and a Cl Ϫ channel (10). Dorwart and colleagues (11) found that WNK kinases inhibited the SLC26A9 Cl Ϫ conductance but that this effect was independent of kinase activity. One group has a preliminary report indicating that WNK3 decreased Cl Ϫ uptake,

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Section: Discussionmentioning

confidence: 99%

Slc26a9 Is Inhibited by the R-region of the Cystic Fibrosis Transmembrane Conductance Regulator via the STAS Domain

Chang

Plata

Sinđić

et al. 2009

Journal of Biological Chemistry

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“…In Vitro Transcription/Translation of Tat1-1 g of Bluescript plasmids containing either Tat1 full-length cDNA or luciferase cDNA were transcribed and translated in the presence of 20 Ci of [ 35 …”

Section: Methodsmentioning

confidence: 99%

“…In Situ Hybridization Experiments-A 1129-base pair fragment of Tat1 cDNA was subcloned in the Bluescript KS plasmid allowing both SP6 and T7 transcription; 35 S-UTP-labeled antisense or sense cRNA probes were obtained by linearizing the plasmid, respectively, by HindIII or BamHI and transcribing with T7 or SP6 RNA polymerase. In the same way, the MgcRacGAP cRNA antisense probe was generated by linearizing a pExLox plasmid containing a 1837-base pair cDNA fragment with KpnI and transcribing with SP6 polymerase as described previously (5).…”

Section: Methodsmentioning

confidence: 99%

“…Strikingly, mutations in all three corresponding genes Dra, DTD, and PDS are responsible for human diseases, i.e. congenital chloride diarrhea (28), diastrophic dysplasia (27,35,36), and goiter associated with congenital deafness known as Pendred syndrome (26,37), respectively. This implies that each of these genes plays a specific and essential role in affected tissues.…”

Section: Tat1 a Male Germ Cell-specific Sulfate Transportermentioning

confidence: 99%

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Tat1, a Novel Sulfate Transporter Specifically Expressed in Human Male Germ Cells and Potentially Linked to RhoGTPase Signaling

Touré

Morin

Pineau

et al. 2001

Journal of Biological Chemistry

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RhoGTPases (Rho, Rac, and Cdc42) are known to regulate multiple functions, including cell motility, adhesion, and proliferation; however, the signaling pathways underlying these pleiotropic effects are far from fully understood. We have recently described a new RhoGAP (GTPase activating protein for RhoGTPases) gene, MgcRacGAP, primarily expressed in male germ cells, at the spermatocyte stage. We report here the isolation, through two-hybrid cloning, of a new partner of MgcRacGAP, very specifically expressed in the male germ line and showing structural features of anion transporters. This large protein (970 amino acids and a predicted size of 109 kDa), we provisionally designated Tat1 (for testis anion transporter 1), is closely related to a sulfate permease family comprising three proteins in human (DRA, Pendrin, and DTD); it is predicted to be an integral membrane protein with 14 transmembrane helices and intracytoplasmic NH 2 and COOH termini. In situ hybridization studies demonstrate that Tat1 and MgcRacGAP genes are coexpressed in male germ cells at the spermatocyte stage. On testis sections, Tat1 protein can be immunodetected in spermatocytes and spermatids associated with plasma membrane. Two-hybrid and in vitro binding assays demonstrate that MgcRacGAP stably interacts through its NH 2 -terminal domain with the Tat1 COOH-terminal region. Expression of Tat1 protein in COS7 cells generates a 4,4-diisothiocyano-2,2-disulfonic acid stilbene and chloride-sensitive sulfate transport. Therefore we conclude that Tat1 is a novel sulfate transporter specifically expressed in spermatocytes and spermatids and interacts with MgcRacGAP in these cells. These observations raise the possibility of a new regulatory pathway linking sulfate transport to Rho signaling in male germ cells.

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“…An independent positional cloning project led to the realization that the immediately adjacent gene SLC26A4/PDS, likely a product of gene duplication, is responsible for both Pendred Syndrome [1] and for nonsyndromic deafness DFNB4 associated with enlargement of the vestibular aqueduct (reviewed by Ito et al [42] in this volume). The unlinked SLC26A2/DTDST gene was next linked to diastrophic dysplasia [43] and several related clinical entities encoded by mutations in the same gene. The above human disease phenotypes have been replicated in knockout mice.…”

Section: Slc26 Anion Transporter Stas Domainsmentioning

confidence: 99%

STAS Domain Structure and Function

Sharma¹,

Rigby²,

Alper³

2011

Cell Physiol Biochem

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Pendrin shares with nearly all SLC26/SulP anion transporters a carboxy-terminal cytoplasmic segment organized around a Sulfate Transporter and Anti-Sigma factor antagonist (STAS) domain. STAS domains of divergent amino acid sequence exhibit a conserved fold of 4 β strands interspersed among 5 α helices. The first STAS domain proteins studied were single-domain anti-sigma factor antagonists (anti-anti-σ). These anti-anti-σ indirectly stimulate bacterial RNA polymerase by inactivating inhibitory anti-σ kinases, liberating σ factors to direct specific transcription of target genes or operons. Some STAS domains are nucleotide-binding phosphoproteins or nucleotidases. Others are interaction/transduction modules within multidomain sensors of light, oxygen and other gasotransmitters, cyclic nucleotides, inositol phosphates, and G proteins. Additional multidomain STAS protein sequences suggest functions in sensing, metabolism, or transport of nutrients such as sugars, amino acids, lipids, anions, vitamins, or hydrocarbons. Still other multidomain STAS polypeptides include histidine and serine/threonine kinase domains and ligand-activated transcription factor domains. SulP/SLC26 STAS domains and adjacent sequences interact with other transporters, cytoskeletal scaffolds, and with enzymes metabolizing transported anion substrates, forming putative metabolons. STAS domains are central to membrane targeting of many SulP/SLC26 anion transporters, and STAS domain mutations are associated with at least three human recessive diseases. This review summarizes STAS domain structure and function.

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Identification of the Finnish founder mutation for diastrophic dysplasia (DTD)

Cited by 55 publications

References 21 publications

Slc26a9 Is Inhibited by the R-region of the Cystic Fibrosis Transmembrane Conductance Regulator via the STAS Domain

Slc26a9 Is Inhibited by the R-region of the Cystic Fibrosis Transmembrane Conductance Regulator via the STAS Domain

Tat1, a Novel Sulfate Transporter Specifically Expressed in Human Male Germ Cells and Potentially Linked to RhoGTPase Signaling

STAS Domain Structure and Function

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