Congenital Chloride-losing Diarrhea Causing Mutations in the STAS Domain Result in Misfolding and Mistrafficking of SLC26A3

Dorwart, Michael R.; Shcheynikov, Nikolay; Baker, Jennifer M.; Forman-Kay, Julie D.; Muallem, Shmuel; Thomas, Philip

doi:10.1074/jbc.m704328200

Cited by 64 publications

(80 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3E), which is known to be required for both the activity and biosynthesis/stability of the transporter. Indeed, other mutations at conserved positions in the STAS domain have been shown to cause congenital chloride diarrhea (23). This mutation was absent among 190 control chromosomes.…”

Section: Mutation In Slc26a3mentioning

confidence: 99%

Genetic diagnosis by whole exome capture and massively parallel DNA sequencing

Choi

Scholl²,

Ji³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

1,187

876

View full text Add to dashboard Cite

Protein coding genes constitute only approximately 1% of the human genome but harbor 85% of the mutations with large effects on disease-related traits. Therefore, efficient strategies for selectively sequencing complete coding regions (i.e., ''whole exome'') have the potential to contribute to the understanding of rare and common human diseases. Here we report a method for whole-exome sequencing coupling Roche/NimbleGen whole exome arrays to the Illumina DNA sequencing platform. We demonstrate the ability to capture approximately 95% of the targeted coding sequences with high sensitivity and specificity for detection of homozygous and heterozygous variants. We illustrate the utility of this approach by making an unanticipated genetic diagnosis of congenital chloride diarrhea in a patient referred with a suspected diagnosis of Bartter syndrome, a renal salt-wasting disease. The molecular diagnosis was based on the finding of a homozygous missense D652N mutation at a position in SLC26A3 (the known congenital chloride diarrhea locus) that is virtually completely conserved in orthologues and paralogues from invertebrates to humans, and clinical follow-up confirmed the diagnosis. To our knowledge, whole-exome (or genome) sequencing has not previously been used to make a genetic diagnosis. Five additional patients suspected to have Bartter syndrome but who did not have mutations in known genes for this disease had homozygous deleterious mutations in SLC26A3. These results demonstrate the clinical utility of whole-exome sequencing and have implications for disease gene discovery and clinical diagnosis.Bartter syndrome ͉ congenital chloride diarrhea ͉ next-generation sequencing ͉ whole-exome sequencing ͉ personal genomes G enetic variation plays a major role in both Mendelian and non-Mendelian diseases. Among the approximately 2,600 Mendelian diseases that have been solved, the overwhelming majority are caused by rare mutations that affect the function of individual proteins; at individual Mendelian loci, approximately 85% of the disease-causing mutations can typically be found in the coding region or in canonical splice sites (1). For complex traits, genome-wide association studies have identified more than 250 common variants associated with risk alleles that contribute to a wide range of diseases (2, 3). To date, most of these impart small effects on disease risk (e.g., odds ratio of 1.2); moreover, even when extremely large studies have been performed, the vast majority of the genetic contribution to disease risk remain unexplained (4-6). These findings suggest that individually rare variants with relatively large effect may account for a large fraction of this missing trait variance. Indeed, studies addressing this question have documented the presence of individually rare variants with relatively large effect (7,8). Consistent with the Mendelian model, coding variants have proven to be prevalent sources of such rare variants.These considerations motivate implementation of robust approaches to sequencing complete c...

show abstract

Section: Mutation In Slc26a3mentioning

confidence: 99%

Genetic diagnosis by whole exome capture and massively parallel DNA sequencing

Choi

Scholl²,

Ji³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

1,187

876

View full text Add to dashboard Cite

show abstract

“…Second, mutations of the N-terminal end of the ␣-helical regions was associated with impaired function despite expression at the plasma membrane (64). A more recent study of disease-associated mutations in the STAS domain of SLC26A3 indicates a predominant effect on biosynthesis, affecting different steps in the folding and/or trafficking pathway of the protein (16). We have also found that single nucleotide polymorphisms in human SLC26A9 flank the STAS domain and that at least one seems to reduce SLC26A9-mediated transport (65).…”

Section: And E)mentioning

confidence: 99%

“…Slc26a9 protein has been localized to epithelia of the stomach and lung (9,10,14), although mRNA is also detectable in brain, heart, kidney, small intestine, thymus, and ovary (10). The R-region of CFTR was previously shown to increase the activity of Slc26a3 and Slc26a6 by interaction with STAS domains (6,15,16). Because Slc26a9 displays several different modes of ion transport, we asked if the R-region of CFTR would also increase the activity of Slc26a9.…”

mentioning

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

View full text Add to dashboard Cite

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,

show abstract

“…The mechanistic role of SpoIIAA phosphorylation remains unclear, because substitution of this serine residue by acidic residues did not phenocopy the activity of serine phosphorylation (24,25,27). The STAS domains of human SLC26A3 (29) and human SLC26A9 (53) interact in vitro with the phosphorylated R domain of CFTR, but the reported regulatory interactions of SLC26 polypeptides and CFTR in vitro and in vivo have varied. PKC phosphorylation of the human SLC26A6 STAS domain has been suggested to regulate Cl Ϫ /HCO 3 Ϫ exchange activity through CAII binding (54), but this phosphorylation did not regulate oxalate transport (55), and its relationship to CFTR is unknown.…”

mentioning

confidence: 99%

“…Published prelim-inary structures of additional STAS domain proteins include the NMR solution structure of Thermotoga maritima putative anti-antagonist TM1442 in phosphorylated and unphosphorylated states (26), the NMR and crystal structures of T. maritima putative anti-antagonist TM1081 (27), and the crystal structure of the putative stressosome component RsbS from Moorella thermoacetica (28). The SpoIIAA structure has been used to model the eukaryotic SLC26 STAS domain, including congenital chloride diarrhea missense mutations in the human SLC26A3 domain that result in subtle chemical shift changes as detected by 1 H-15 N two-dimensional HSQC NMR (29). However, the amino acid assignments of this structure have not been reported and, until recently, no other structural information had been released for STAS domains of SulP/SLC26 anion transporters.…”

mentioning

confidence: 99%

Solution Structure of the Guanine Nucleotide-binding STAS Domain of SLC26-related SulP Protein Rv1739c from Mycobacterium tuberculosis

Sharma

Baer

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

The structure and intrinsic activities of conserved STAS domains of the ubiquitous SulP/SLC26 anion transporter superfamily have until recently remained unknown. Here we report the heteronuclear, multidimensional NMR spectroscopy solution structure of the STAS domain from the SulP/SLC26 putative anion transporter Rv1739c of Mycobacterium tuberculosis. The 0.87-Å root mean square deviation structure revealed a four-stranded ␤-sheet with five interspersed ␣-helices, resembling the anti-factor antagonist fold. Rv1739c STAS was shown to be a guanine nucleotide-binding protein, as revealed by nucleotide-dependent quench of intrinsic STAS fluorescence and photoaffinity labeling. NMR chemical shift perturbation analysis partnered with in silico docking calculations identified solvent-exposed STAS residues involved in nucleotide binding. Rv1739c STAS was not an in vitro substrate of mycobacterial kinases or anti-factors. These results demonstrate that Rv1739c STAS binds guanine nucleotides at physiological concentrations and undergoes a ligand-induced conformational change but, unlike anti-factor antagonists, may not mediate signals via phosphorylation.

show abstract

Congenital Chloride-losing Diarrhea Causing Mutations in the STAS Domain Result in Misfolding and Mistrafficking of SLC26A3

Cited by 64 publications

References 63 publications

Genetic diagnosis by whole exome capture and massively parallel DNA sequencing

Genetic diagnosis by whole exome capture and massively parallel DNA sequencing

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

Solution Structure of the Guanine Nucleotide-binding STAS Domain of SLC26-related SulP Protein Rv1739c from Mycobacterium tuberculosis

Contact Info

Product

Resources

About