Alternative titles; symbols
HGNC Approved Gene Symbol: SLC26A3
SNOMEDCT: 24412005;
Cytogenetic location: 7q22.3-q31.1 Genomic coordinates (GRCh38): 7:107,765,469-107,803,223 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q22.3-q31.1 | Diarrhea 1, secretory chloride, congenital | 214700 | Autosomal recessive | 3 |
SLC26A3 functions as a chloride/bicarbonate exchanger and is highly expressed in gastrointestinal, pancreatic, and renal tissues (summary by El Khouri et al., 2018).
By subtractive hybridization, Schweinfest et al. (1993) isolated a cDNA for a tumor suppressor candidate gene, which they called DRA (downregulated in adenoma), from a normal colon tissue cDNA library. Its expression, which appeared to be limited to the mucosa of normal colon, was significantly decreased in adenomas and adenocarcinomas of the colon and was downregulated early in tumorigenesis.
Dorwart et al. (2008) showed that SLC26A3 was highly glycosylated and that both the N and C termini of SLC26A3 were cytosolic.
Haila et al. (1998) found that the CLD/DRA gene spans approximately 39 kb and comprises 21 exons. All exon/intron boundaries conformed to the GT/AG rule. Genomic sequencing of a BAC clone revealed the presence of another, highly homologous gene 3-prime of the CLD gene, with a similar genomic structure, identified as the Pendred syndrome gene (SLC26A4; 605646).
By somatic cell hybridization and use of a cDNA probe, Schweinfest et al. (1993) assigned the DRA gene, which was present in single copy, to chromosome 7. Based on the structure of the predicted 84-kD DRA polypeptide, Schweinfest et al. (1993) suggested that DRA is a transcription factor or a protein that interacts with transcription factors. By fluorescence in situ hybridization, Taguchi et al. (1994) refined the assignment to 7q22-q31.1. The small intestinal mucin-3 gene (158371) is located in the same region.
Hoglund et al. (1996) found 2 missense mutations and 1 frameshift mutation in the DRA gene in 32 Finnish and 4 Polish congenital chloride diarrhea (DIAR1; 214700) patients. The disease-causing nature of the val317-to-del missense mutation (126650.0001) was supported by genetic data in relation to the population history of Finland. By mRNA in situ hybridization, Hoglund et al. (1996) demonstrated that the expression of DRA occurs preferentially in highly differentiated colonic epithelial cells and is low in undifferentiated (including neoplastic) cells. The expression of DRA is unchanged in Finnish DIAR1 patients with the val317-to-del mutation; however, the function of the mutant protein must be severely impaired. The finding of low DRA expression in neoplastic cells had previously been taken as a suggestion that DRA is a tumor suppressor; clearly, the low expression is related solely to the undifferentiated state of the neoplastic cells. The demonstration of the relationship between DRA mutations and chloride diarrhea indicated that DRA is an intestinal and transport molecule.
As noted in 126650.0001, all cases of chloride diarrhea (CLD) in the Finnish founder population studied by Hoglund et al. (1996) had a 3-bp deletion resulting in the loss of valine-317 in the predicted CLD/DRA protein. Two additional mutations, H124L (126650.0002) and 344delT (126650.0003), were found in Polish CLD patients. Hoglund et al. (1998) screened for additional mutations in a set of 14 CLD families of Polish, Swedish, North American, and Finnish origin, using primers that allowed mutation searches directly from genomic DNA samples. They found 8 novel mutations, including 2 transversions, 1 transition, 1 insertion, and 4 small deletions. They pointed out that of 11 sequence alterations detected to that time, 9 lie clustered in 3 short segments of 49 bp, 39 bp, and 65 bp, respectively. These short segments span only 6.7% of the total cDNA length, suggesting functional importance or mutation-prone DNA regions of the corresponding CLD/DRA protein domains.
Hoglund et al. (2001) stated that a total of 3 founder and 17 private mutations underlying congenital chloride diarrhea had been described in various ethnic groups. They screened for mutations in 7 unrelated families with CLD and found 7 novel mutations as well as 2 previously identified ones. They reported for the first time rearrangement mutations in SLC26A3 (see 126650.0004). Molecular features predisposing SLC26A3 for the 2 rearrangements may include repetitive elements and palindromic-like sequences.
Makela et al. (2002) noted that the only extraintestinal tissues showing SLC26A3 expression are eccrine sweat glands and seminal vesicles. They presented a summary of published mutations and polymorphisms of the SLC26A3 gene and reported 2 novel mutations of the gene: a 13-bp deletion (126650.0007) and a trp462-to-ter change (W462X; 126650.0008). The authors described the geographic and population distributions of 3 founder mutations: the Finnish V317del mutation (126650.0001), the Polish I675-676ins mutation (126650.0005), and the Arab gly187-to-ter mutation (G187X; 126650.0006). They also tabulated genetic disorders with congenital or neonatal diarrhea as a main symptom.
Choi et al. (2009) used whole-exome capture and massively parallel DNA sequencing to identify a homozygous pathogenic mutation in the SLC26A3 gene in a Turkish infant with congenital chloride diarrhea who was initially thought to have renal Bartter syndrome. Sequencing this gene in 39 additional patients referred with a suspected diagnosis of Bartter syndrome identified recessive SLC26A3 mutations in 5 patients. All except 1 presented in infancy with watery diarrhea associated with hypokalemia, increased serum bicarbonate, and high aldosterone. High stool chloride was documented in 2 patients studied. Choi et al. (2009) emphasized the utility of this novel approach for the identification of pathogenic mutations.
Ben-David et al. (2019) identified homozygosity for a 1-bp deletion (126650.0009) in the SLC26A3 gene in a 10-year-old Arab girl, born to consanguineous parents, with DIAR1. The patient was initially thought to have Bartter syndrome but molecular causes of that disorder were excluded. The SLC26A3 mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. The parents were heterozygous for the mutation.
Schweinfest et al. (2006) found that Slc26a3 -/- mice showed postpartum lethality at low penetrance. Surviving Slc26a3 -/- mice exhibited high chloride content diarrhea and growth retardation. Large intestinal loops were distended, and colonic mucosa showed aberrant growth. Ion transport was abnormal, with upregulation of epithelial sodium channel (see 600228) in distal colon and Nhe3 (SLC9A3; 182307) in both proximal and distal colon. The authors concluded that SLC26A3 is the major chloride/base exchanger in colon and is necessary for absorption of chloride.
Kini et al. (2022) found that microbiota of Slc26a3 -/- mice had reduced diversity, fewer short-chain fatty acid producers, and increased pathobionts.
El Khouri et al. (2018) found that male Slc26a3 -/- mice had severe lesions and abnormal cytoarchitecture of epididymis, along with reduced sperm count and infertility. Sperm were immotile and showed impaired capacitation, a phenotype the authors characterized as oligoasthenoteratozoospermia.
Hoglund et al. (1996) found that all of 32 Finnish patients with CLD (DIAR1; 214700) were homozygous for a 3-bp deletion that resulted in deletion of valine-317 with no frameshift. In eastern Finland from whence the cases were derived, heterozygosity for the val317-to-del mutation was found in 3 of 452 individuals (in 3 of 504 chromosomes) and in none of 368 chromosomes from southwestern Finland where the frequency of CLD is much lower. The mutation consisted of loss of GGT beginning with nucleotide 951 of the cDNA. Sequencing of the coding region of DRA in a Finnish patient revealed an additional T-to-G transversion at position 921, 30 bp upstream of codon 317. This change also occurred in homozygous form in all 32 Finnish individuals affected with CLD, and in heterozygous form in all 43 parents. However, it was found in homozygous form in an unaffected sib of a patient and in a control individual, suggesting that it is not, or is not alone, disease-causing, but rather a functionally neutral polymorphism.
In 2 Polish patients with congenital chloride diarrhea (DIAR1; 214700), Hoglund et al. (1996) demonstrated an A-to-T transversion at nucleotide 371 of the DRA gene, leading to a his124-to-leu (H124L) substitution.
In 2 Polish patients with congenital chloride diarrhea (DIAR1; 214700), Hoglund et al. (1996) demonstrated homozygosity for a deletion at nucleotide 344, a T in codon 115, leading to a frameshift and stop at codon 133.
The first large rearrangement of the SLC26A3 gene was identified by Hoglund et al. (2001) in 2 Japanese sibs, whose clinical presentation of congenital chloride diarrhea (DIAR1; 214700) was reported by Yoshikawa et al. (2000). Both were homozygous for a 3.5-kb genomic deletion that included exons 7 and 8. The deletion disrupted the open reading frame and caused truncation of the polypeptide chain after 32% of its normal length. The surrounding genome contains an array of repetitive elements.
Hoglund et al. (1998) described an in-frame addition of an ATC (ile) in exon 18 of the SLC26A3 gene, constituting codon 676, in 12 Polish cases of congenital chloride diarrhea (DIAR1; 214700) and constituting the 'Polish founder mutation.'
Dorwart et al. (2008) showed that the ile676 insertion results in the misfolding of the STAS domain of SLC26A3. Mutant SLC26A3 accumulated in the endoplasmic reticulum rather being transported to the plasma membrane, and it was rapidly degraded.
In 11 cases of congenital chloride diarrhea (DIAR1; 214700) in Saudi Arabia, Kuwait, and the U.K., Hoglund et al. (1998) identified a gly187-to-ter (G187X) mutation in the SLC26A3 gene. This was designated the Arabic founder mutation.
In a Belgian patient, whose parents were both African in origin, Makela et al. (2002) identified the molecular basis of congenital chloride diarrhea (DIAR1; 214700) to be a 13-bp deletion of nucleotides 145-157 in exon 3 of the SLC26A3 gene.
In a patient from the U.K. with congenital chloride diarrhea (DIAR1; 214700), Makela et al. (2002) identified a 1386G-A transition in exon 12 of the SLC26A3 gene resulting in a trp462-to-ter (W462X) mutation. The patient's parents were of Arab ancestry and were not known to be consanguineous.
In a 10-year-old Arab girl, born to consanguineous parents, with congenital chloride diarrhea (DIAR1; 214700), Ben-David et al. (2019) identified homozygosity for a 1-bp deletion (c.1652delT, NM_000111.2) in the SLC26A3 gene, predicted to cause a frameshift and premature termination (Phe551fsTer25). The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. The parents were confirmed to be carriers. Functional studies were not performed.
Ben-David, Y., Halevy, R., Sakran, W., Zehavi, Y., Spiegel, R. The utility of next generation sequencing in the correct diagnosis of congenital hypochloremic hypokalemic metabolic alkalosis. Europ. J. Med. Genet. 62: 103728, 2019. Note: Electronic Article. [PubMed: 31325522] [Full Text: https://doi.org/10.1016/j.ejmg.2019.103728]
Choi, M., Scholl, U. I., Ji, W., Liu, T., Tikhonova, I. R., Zumbo, P., Nayir, A., Bakkaloglu, A., Ozen, S., Sanjad, S., Nelson-Williams, C., Farhi, A., Mane, S., Lifton, R. P. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc. Nat. Acad. Sci. 106: 19096-19101, 2009. [PubMed: 19861545] [Full Text: https://doi.org/10.1073/pnas.0910672106]
Dorwart, M. R., Shcheynikov, N., Baker, J. M. R., Forman-Kay, J. D., Muallem, S., Thomas, P. J. Congenital chloride-losing diarrhea causing mutations in the STAS domain result in misfolding and mistrafficking of SLC26A3. J. Biol. Chem. 283: 8711-8722, 2008. [PubMed: 18216024] [Full Text: https://doi.org/10.1074/jbc.M704328200]
El Khouri, E., Whitfield, M., Stouvenel, L., Kini, A., Riederer, B., Lores, P., Roemermann, D., di Stefano, G., Drevet, J. R., Saez, F., Seidler, U., Toure, A. Slc26a3 deficiency is associated with epididymis dysplasia and impaired sperm fertilization potential in the mouse. Molec. Reprod. Dev. 85: 682-695, 2018. [PubMed: 30118583] [Full Text: https://doi.org/10.1002/mrd.23055]
Haila, S., Hoglund, P., Scherer, S. W., Lee, J. R., Kristo, P., Coyle, B., Trembath, R., Holmberg, C., de la Chapelle, A., Kere, J. Genomic structure of the human congenital chloride diarrhea (CLD) gene. Gene 214: 87-93, 1998. [PubMed: 9729124] [Full Text: https://doi.org/10.1016/s0378-1119(98)00261-3]
Hoglund, P., Auranen, M., Socha, J., Popinska, K., Nazer, H., Rajaram, U., Al Sanie, A., Al-Ghanim, M., Holmberg, C, de la Chapelle, A., Kere, J. Genetic background of congenital chloride diarrhea in high-incidence populations: Finland, Poland, and Saudi Arabia and Kuwait. Am. J. Hum. Genet. 63: 760-768, 1998. [PubMed: 9718329] [Full Text: https://doi.org/10.1086/301998]
Hoglund, P., Haila, S., Gustavson, K.-H., Taipale, M., Hannula, K., Popinska, K., Holmberg, C., Socha, J., de la Chapelle, A., Kere, J. Clustering of private mutations in the congenital chloride diarrhea/down-regulated in adenoma gene. Hum. Mutat. 11: 321-327, 1998. [PubMed: 9554749] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1998)11:4<321::AID-HUMU10>3.0.CO;2-A]
Hoglund, P., Haila, S., Socha, J., Tomaszewski, L., Saarialho-Kere, U., Karjalainen-Lindsberg, M.-L., Airola, K., Holmberg, C., de la Chapelle, A., Kere, J. Mutations of the down-regulated in adenoma (DRA) gene cause congenital chloride diarrhoea. Nature Genet. 14: 316-319, 1996. [PubMed: 8896562] [Full Text: https://doi.org/10.1038/ng1196-316]
Hoglund, P., Sormaala, M., Haila, S., Socha, J., Rajaram, U., Scheurlen, W., Sinaasappel, M., de Jonge, H., Holmberg, C., Yoshikawa, H., Kere, J. Identification of seven novel mutations including the first two genomic rearrangements in SLC26A3 mutated in congenital chloride diarrhea. Hum. Mutat. 18: 233-242, 2001. [PubMed: 11524734] [Full Text: https://doi.org/10.1002/humu.1179]
Kini, A., Zhao, B., Basic, M., Roy, U., Iljazovic, A., Odak, I., Ye, Z., Riederer, B., Di Stefano, G., Romermann, D., Koenecke, C., Bleich, A., Strowig, T., Seidler, U. Upregulation of antimicrobial peptide expression in slc26a3-/- mice with colonic dysbiosis and barrier defect. Gut Microbes 14: e2041943, 2022.
Makela, S., Kere, J., Holmberg, C., Hoglund, P. SLC26A3 mutations in congenital chloride diarrhea. Hum. Mutat. 20: 425-438, 2002. [PubMed: 12442266] [Full Text: https://doi.org/10.1002/humu.10139]
Schweinfest, C. W., Henderson, K. W., Suster, S., Kondoh, N., Papas, T. S. Identification of a colon mucosa gene that is down-regulated in colon adenomas and adenocarcinomas. Proc. Nat. Acad. Sci. 90: 4166-4170, 1993. [PubMed: 7683425] [Full Text: https://doi.org/10.1073/pnas.90.9.4166]
Schweinfest, C. W., Spyropoulos, D. D., Henderson, K. W., Kim, J.-H., Chapman, J. M., Barone, S., Worrell, R. T., Wang, Z., Soleimani, M. slc26a3 (dra)-deficient mice display chloride-losing diarrhea, enhanced colonic proliferation, and distinct up-regulation of ion transporters in the colon. J. Biol. Chem. 281: 37962-37971, 2006. [PubMed: 17001077] [Full Text: https://doi.org/10.1074/jbc.M607527200]
Taguchi, T., Testa, J. R., Papas, T. S., Schweinfest, C. Localization of a candidate colon tumor-suppressor gene (DRA) to 7q22-q31.1 by fluorescence in situ hybridization. Genomics 20: 146-147, 1994. [PubMed: 8020951] [Full Text: https://doi.org/10.1006/geno.1994.1148]
Yoshikawa, H., Watanabe, T., Abe, T., Sato, M., Oda, Y. Japanese siblings with congenital chloride diarrhea. Pediatr. Int. 42: 313-315, 2000. [PubMed: 10881594] [Full Text: https://doi.org/10.1046/j.1442-200x.2000.01215.x]