Disease relevance of SLC26A4

• Of nine known human genes in this family, three (SLC26A2, SLC26A3 and SLC26A4) are associated with different human hereditary diseases [1].
• SLC26A4 gene methylation in benign adenomas and the relatively well-differentiated WRO cell line suggest that this alteration is an early event in thyroid tumorigenesis [2].
• Intrafamilial variability of the deafness and goiter phenotype in Pendred syndrome caused by a T416P mutation in the SLC26A4 gene [3].
• SLC26A4 gene is frequently involved in nonsyndromic hearing impairment with enlarged vestibular aqueduct in Caucasian populations [4].
• We were unable to detect evidence of sulfate transport following the expression of pendrin in Xenopus laevis oocytes by microinjection of PDS cRNA or in Sf9 cells following infection with PDS-recombinant baculovirus [5].
• The study identifies pendrin as a novel autoantigen recognized by patients with autoimmune thyroid diseases and proposes the use of pendrin antibodies as an accurate diagnostic tool [6].

Psychiatry related information on SLC26A4

• The potential advantages of PDS II-augmented refixation of acute proximal ACL ruptures are anatomic reconstruction without destruction of other anatomic structures used as grafts, early functional rehabilitation and possibly better proprioception [7].
• Experts in OCD and PTSD independently rated items on the OCI and PDS for the degree of overlap across the disorders [8].
• All three PDS scale scores were negatively related to symptom endorsement and to the diagnosis of drug dependence [9].
• These findings underline the importance of deception to correctional assessment and the need for more information on the psychometrics and operating characteristics of the PDS in correctional settings [9].
• To study sources of individual differences in pubertal development, the authors fit a sex-limitation common factor model to data reported, at ages 11 and 14 years, by 1,891 twin pairs on items that comprise the Pubertal Development Scale (PDS; A. C. Petersen, L. Crockett, M. Richards, & A. Boxer, 1988) [10].

High impact information on SLC26A4

• On the basis of this homology and the presence of a slightly modified sulfate-transporter signature sequence comprising its putative second transmembrane domain, pendrin has been proposed to function as a sulfate transporter [5].
• Our results demonstrate that pendrin functions as a transporter of chloride and iodide, but not sulfate, and may provide insight into thyroid physiology and the pathophysiology of Pendred syndrome [5].
• The rates of transport for iodide and chloride were significantly increased following the expression of pendrin in both cell systems [5].
• Pendred syndrome (goitre and sensorineural hearing loss) maps to chromosome 7 in the region containing the nonsyndromic deafness gene DFNB4 [11].
• These data raise the possibility that Pendred syndrome is either allelic with DFNB4 or may represent an inherited contiguous gene disorder, not clinically manifest in the heterozygote [11].

Chemical compound and disease context of SLC26A4

• All patients harbouring mutations in the SLC26A4 gene had goiter and a positive perchlorate discharge test: 3 were slightly hypothyroid and 2 euthyroid [12].
• STUDY DESIGN: We completed retrospective mutation screening of GJB2 and SLC26A4 and screened for three mtDNA mutations in patients with a history of childhood cancer who developed severe hearing loss at cumulative cisplatin doses of less than 400 mg/M2 [13].
• The validation of the method was done by functionally characterizing the chloride/iodide transport of SLC26A4, and a mutant, i.e. SLC26A4(S28R), which we previously described in a patient with sensorineural hearing loss, hypothyroidism and goiter [14].
• Pyridoxine-dependent seizure (PDS) is a rare autosomal recessive intractable seizure disorder only controlled by a daily supplementation of pharmacological doses of pyridoxine (Vitamin B6) [15].
• Pendrin protein was detected in 73.3 and 76.7% of the follicular (FTC) and papillary (PTC) thyroid carcinomas, respectively, where pendrin was solely localised inside the cytoplasm [16].

Biological context of SLC26A4

• In total, 7 mutated SLC26A4 alleles, including 6 missense mutations (A372V, A387V, T410M, S448L, T721M, and H723R) and 1 splice site mutation (IVS7-2A-->G), were detected [17].
• A complete evaluation of thyroid function including thyroid echography and perchlorate discharge test was carried out in all patients with EVA; all exons of the SLC26A4 gene were amplified from peripheral leukocytes and directly sequenced, using specific intronic primers [12].
• Mutation of the SLC26A4 gene was identified in five patients: four were compound heterozygous (H723R/919-2A>G, H723R/IVS15+5G>A, H723R/R581S, IVS7-2A>G/IVS8+1G>A), the fifth had a frameshift mutation (322delC) [18].
• SLC26A4 linked haplotypes on chromosomes with recurrent mutations were consistent with founder effects [19].
• Five mutations were novel and the other four had seldom, if ever, been identified outside east Asia. To identify mutations in south Asians, 212 Pakistani and 106 Indian families with three or more affected offspring of consanguineous matings were analysed for cosegregation of recessive deafness with short tandem repeat markers linked to SLC26A4 [19].

Anatomical context of SLC26A4

• Hypermethylation of the Pendred syndrome gene SLC26A4 is an early event in thyroid tumorigenesis [2].
• Mutations in the SLC26A4 gene cause both classical PS and deafness associated with an enlarged vestibular aqueduct without goiter.To investigate a possible genotype-phenotype correlation in PS, we performed a detailed clinical and genetic study in three adult German sibs with typical PS caused by a common homozygous SLC26A4 mutation, T416P [3].
• Specificity of SLC26A4 mutations in the pathogenesis of inner ear malformations [17].
• Current potential candidates for screening include SLC26A4, in the presence of specific temporal bone anomalies, and WFS1, in the presence of a low-frequency hearing loss [20].
• This mutant protein is transposed towards the cell membrane, however, its transport capability is markedly reduced if compared to wild-type SLC26A4 [21].

Associations of SLC26A4 with chemical compounds

• CONCLUSION: Our experiments suggest that the SLC26A4-induced chloride transport is electroneutral when expressed in human cellular systems [22].
• Expression of the SLC26A4 gene may be responsible for iodide transport in the thyroid as well as for formation and function of the inner ear [18].
• A reduced PDS mRNA expression might explain the defective thyroxine (T(4)) production [23].
• Sequence analysis of the PDS gene performed with DNA from the two relatives with Pendred's syndrome revealed the presence of a deletion of thymidine 279 in exon 3, a point mutation that results in a frameshift and a premature stop codon at codon 96 in the pendrin molecule [24].
• SLC26A4 is upregulated with aldosterone analogues and with Cl- restriction [25].

Other interactions of SLC26A4

• Genetically engineered null mice have highlighted the important role of two members of the SLC26 family, SLC26A4 and SLC26A6, in homeostatic function in kidney and/or intestine [26].
• Patients with mutations in the SLC26A4 gene had larger thyroid volume (p<0.002), higher serum thyroglobulin (Tg) levels (p<0.002) and greater radioiodine discharge after perchlorate (p=0.09) than patients without mutations [12].
• Mutations in the SLC26A4 (pendrin) gene in patients with sensorineural deafness and enlarged vestibular aqueduct [12].
• In a further family with 12 members in whom we have previously demonstrated linkage to the MNG-1 locus we investigated the Xp22 locus and the PDS gene in addition to our initial study [27].
• A significant total NPL score of 6.5 for PDS over all families most likely indicated linkage to a genomic region close to PDS [27].

Analytical, diagnostic and therapeutic context of SLC26A4

• METHODS: We overexpressed the human SLC26A4 isoform in HEK293 Phoenix cells and measured cationic and anionic currents by the patch-clamp technique in whole cell configuration [22].
• We PCR amplified and sequenced seven exons of SLC26A4 to detect selected mutations in 274 deaf probands from Korea, China, and Mongolia [19].
• Linkage studies and sequence analysis of the coding region of the PDS gene were performed with DNA from 36 individuals [28].
• METHODS: Perchlorate discharge test, mutation analysis of the SLC26A4 gene, MR imaging of temporal bones, vestibular function test (in two cases) and serial audiometry [29].
• Using immunohistochemistry, pendrin-positive cells were detected on both gill lamellae and interlamellar regions of freshwater stingrays but were more restricted to interlamellar regions in seawater-acclimated and marine stingray gills [30].

References