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|Coordinate||31,525,568 bp (GRCm38)|
|Base Change||A ⇒ T (forward strand)|
|Gene Name||solute carrier family 26, member 4|
|Chromosomal Location||31,519,827-31,559,969 bp (-)|
|MGI Phenotype||Homozygous null mutants are completely deaf with vestibular dysfunction. Mutants show endolymphatic dilatation, degeneration of sensory cells and malformations of otoconia and otoconial membranes. They display unsteady gait and circling and head bobbing.|
|Amino Acid Change||Cysteine changed to Stop codon|
|Institutional Source||Beutler Lab|
|Gene Model||predicted sequence gene model|
AA Change: C706*
|Predicted Effect||probably null|
|Phenotypic Category||behavior/neurological, DSS: sensitive day 10, hearing/vestibular/ear|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Local Stock||Sperm, gDNA|
|Last Updated||03/08/2017 11:11 AM by Anne Murray|
|Record Created||10/24/2014 10:18 AM by Jeff SoRelle|
The cul-de-sac phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R1301, some of which showed head tossing, head tilting, and circling (Figure 1). One mouse also was susceptible to a low dose of DSS (1%) showing weight loss 10 days after DSS treatment (Figure 2).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 57 mutations. Both of the above anomalies were linked by continuous variable mapping to a mutation in Slc26a4: a T to A transversion at base pair 31,525,568 (v38) on chromosome 12, or base pair 35,072 in the GenBank genomic region NC_000078 encoding Slc26a4. The strongest association was found with a recessive model of linkage to the normalized DSS Day 10 reading, wherein one variant homozygote departed phenotypically from 13 homozygous reference mice and 15 heterozygous mice with a P value of 8.731 x 10-7 (Figure 3).
The mutation corresponds to residue 2,333 in the mRNA sequence NM_011867 within exon 19 of 21 total exons.
The mutated nucleotide is indicated in red. The mutation results in substitution of cysteine (C) 706 to a premature stop codon in the pendrin protein.
Slc26a4 encodes pendrin, a 780-amino acid member of solute carrier (SLC) family 26 (Figure 4). The gene products include passive transporters, symporters, and antiporters that transport a wide variety of substrates, including amino acids, oligopeptides, glucose, inorganic cations and anions, bile salts, carboxylate, acetyl coenzyme A, essential metals, neurotransmitters, vitamins, fatty acids, lipids, nucleosides, ammonium, choline, thyroid hormone, and urea (1). SLC family members have a variable number of transmembrane domains; pendrin is predicted to have 12 transmembrane domains (2) with a cytoplasmic N- and C-termini. The C-terminus of pendrin has a STAS (sulfate transporter antagonist of anti-sigma factor) domain (amino acids 536-725) (3). The STAS domain is proposed to mediate NTP binding and/or hydrolysis as well as to regulate anion transport by sensing intracellular concentrations of GTP and/or ATP (3).
The Slc26a4 mutation in cul-de-sac results in substitution of cysteine (C) 706 to a premature stop codon in the pendrin protein. Cys706 resides in the STAS domain.
For more information about Slc26a4, please see the record for discobolus.
Pendrin mediates Cl−/I− or I−/HCO3− exchange in the salivary duct (4), thyrocytes (5), and renal collecting duct (6;7). In the inner ear, pendrin conditions the endolymph to permit the proper function of sensory cells by facilitating Cl−/HCO3− exchange. Mutations in SLC26A4 are linked to autosomal recessive deafness 4 with enlarged vestibular aqueduct (DFNB4 with EVA; OMIM: #600791) and Pendred syndrome (alternatively, Mondini-like dysplasia of the cochlea and enlargement of the thyroid; OMIM: #274600) (8-14). Slc26a4-deficient (Slc26a4-/-) mice develop EVA and Mondini-like dysplasia of the cochlea similar to that observed in Pendred syndrome in humans. The Slc26a4-/- mice are unable to hear and exhibit circling and head bobbing indicative of vestibular defects.
The vestibular phenotype of the cul-de-sac mice mimics that of the Slc26a4 mutant models, indicating that pendrincul-de-sac function is defective in the mice. Expression and localization of pendrincul-de-sac have not been examined. The putative colitis phenotype in the cul-de-sac mice has not been confirmed.
cul-de-sac(F):5'- CCAGAGGTTAAGCTGGGTTTCAGAC -3'
cul-de-sac(R):5'- CATTAGGCAAAGCTGCTCAAGCAC -3'
cul-de-sac_seq(F):5'- TAAGCTGGGTTTCAGACTAGAG -3'
cul-de-sac_seq(R):5'- gctgggggatggaatcac -3'
1. He, L., Vasiliou, K., and Nebert, D. W. (2009) Analysis and Update of the Human Solute Carrier (SLC) Gene Superfamily. Hum Genomics. 3, 195-206.
2. Li, J., Xia, F., and Reithmeier, R. A. (2014) N-Glycosylation and Topology of the Human SLC26 Family of Anion Transport Membrane Proteins. Am J Physiol Cell Physiol. 306, C943-60.
3. Aravind, L., and Koonin, E. V. (2000) The STAS Domain - a Link between Anion Transporters and Antisigma-Factor Antagonists. Curr Biol. 10, R53-5.
4. Shcheynikov, N., Yang, D., Wang, Y., Zeng, W., Karniski, L. P., So, I., Wall, S. M., and Muallem, S. (2008) The Slc26a4 Transporter Functions as an Electroneutral Cl-/I-/HCO3- Exchanger: Role of Slc26a4 and Slc26a6 in I- and HCO3- Secretion and in Regulation of CFTR in the Parotid Duct. J Physiol. 586, 3813-3824.
5. Pesce, L., Bizhanova, A., Caraballo, J. C., Westphal, W., Butti, M. L., Comellas, A., and Kopp, P. (2012) TSH Regulates Pendrin Membrane Abundance and Enhances Iodide Efflux in Thyroid Cells. Endocrinology. 153, 512-521.
6. Royaux, I. E., Wall, S. M., Karniski, L. P., Everett, L. A., Suzuki, K., Knepper, M. A., and Green, E. D. (2001) Pendrin, Encoded by the Pendred Syndrome Gene, Resides in the Apical Region of Renal Intercalated Cells and Mediates Bicarbonate Secretion. Proc Natl Acad Sci U S A. 98, 4221-4226.
7. Kim, Y. H., Pham, T. D., Zheng, W., Hong, S., Baylis, C., Pech, V., Beierwaltes, W. H., Farley, D. B., Braverman, L. E., Verlander, J. W., and Wall, S. M. (2009) Role of Pendrin in Iodide Balance: Going with the Flow. Am J Physiol Renal Physiol. 297, F1069-79.
8. Albert, S., Blons, H., Jonard, L., Feldmann, D., Chauvin, P., Loundon, N., Sergent-Allaoui, A., Houang, M., Joannard, A., Schmerber, S., Delobel, B., Leman, J., Journel, H., Catros, H., Dollfus, H., Eliot, M. M., David, A., Calais, C., Drouin-Garraud, V., Obstoy, M. F., Tran Ba Huy, P., Lacombe, D., Duriez, F., Francannet, C., Bitoun, P., Petit, C., Garabedian, E. N., Couderc, R., Marlin, S., and Denoyelle, F. (2006) SLC26A4 Gene is Frequently Involved in Nonsyndromic Hearing Impairment with Enlarged Vestibular Aqueduct in Caucasian Populations. Eur J Hum Genet. 14, 773-779.
9. Anwar, S., Riazuddin, S., Ahmed, Z. M., Tasneem, S., Ateeq-ul-Jaleel, Khan, S. Y., Griffith, A. J., Friedman, T. B., and Riazuddin, S. (2009) SLC26A4 Mutation Spectrum Associated with DFNB4 Deafness and Pendred's Syndrome in Pakistanis. J Hum Genet. 54, 266-270.
10. Li, X. C., Everett, L. A., Lalwani, A. K., Desmukh, D., Friedman, T. B., Green, E. D., and Wilcox, E. R. (1998) A Mutation in PDS Causes Non-Syndromic Recessive Deafness. Nat Genet. 18, 215-217.
11. Choi, B. Y., Stewart, A. K., Madeo, A. C., Pryor, S. P., Lenhard, S., Kittles, R., Eisenman, D., Kim, H. J., Niparko, J., Thomsen, J., Arnos, K. S., Nance, W. E., King, K. A., Zalewski, C. K., Brewer, C. C., Shawker, T., Reynolds, J. C., Butman, J. A., Karniski, L. P., Alper, S. L., and Griffith, A. J. (2009) Hypo-Functional SLC26A4 Variants Associated with Nonsyndromic Hearing Loss and Enlargement of the Vestibular Aqueduct: Genotype-Phenotype Correlation Or Coincidental Polymorphisms? Hum Mutat. 30, 599-608.
12. Campbell, C., Cucci, R. A., Prasad, S., Green, G. E., Edeal, J. B., Galer, C. E., Karniski, L. P., Sheffield, V. C., and Smith, R. J. (2001) Pendred Syndrome, DFNB4, and PDS/SLC26A4 Identification of Eight Novel Mutations and Possible Genotype-Phenotype Correlations. Hum Mutat. 17, 403-411.
13. Everett, L. A., Glaser, B., Beck, J. C., Idol, J. R., Buchs, A., Heyman, M., Adawi, F., Hazani, E., Nassir, E., Baxevanis, A. D., Sheffield, V. C., and Green, E. D. (1997) Pendred Syndrome is Caused by Mutations in a Putative Sulphate Transporter Gene (PDS). Nat Genet. 17, 411-422.
|Science Writers||Anne Murray|
|Illustrators||Peter Jurek, Katherine Timer|
|Authors||Jeff SoRelle, Emre Turer, Noelle Hutchins, William McAlpine|
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