Transcriptional Control of SLC26A4 Is Involved in Pendred Syndrome and Nonsyndromic Enlargement of Vestibular Aqueduct (DFNB4)

Department of Otolaryngology-Head and Neck, University of Iowa, Iowa City, IA 52242, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 07/2007; 80(6):1055-63. DOI: 10.1086/518314
Source: PubMed


Although recessive mutations in the anion transporter gene SLC26A4 are known to be responsible for Pendred syndrome (PS) and nonsyndromic hearing loss associated with enlarged vestibular aqueduct (EVA), also known as "DFNB4," a large percentage of patients with this phenotype lack mutations in the SLC26A4 coding region in one or both alleles. We have identified and characterized a key transcriptional regulatory element in the SLC26A4 promoter that binds FOXI1, a transcriptional activator of SLC26A4. In nine patients with PS or nonsyndromic EVA, a novel c.-103T-->C mutation in this regulatory element interferes with FOXI1 binding and completely abolishes FOXI1-mediated transcriptional activation. We have also identified six patients with mutations in FOXI1 that compromise its ability to activate SLC26A4 transcription. In one family, the EVA phenotype segregates in a double-heterozygous mode in the affected individual who carries single mutations in both SLC26A4 and FOXI1. This finding is consistent with our observation that EVA occurs in the Slc26a4(+/-); Foxi1(+/-) double-heterozygous mouse mutant. These results support a novel dosage-dependent model for the molecular pathogenesis of PS and nonsyndromic EVA that involves SLC26A4 and its transcriptional regulatory machinery.

14 Reads
  • Source
    • "The autosomal recessive inheritance of PDS and DFNB4 is well established and yet, for many affected individuals, analysis of the coding sequences and splice sites of the SLC26A4 gene has failed to identify one or both of the mutations required to cause these disorders (Campbell et al., 2001; Tsukamoto et al., 2003; Pryor et al., 2005; Albert et al., 2006; Yang et al., 2007; Wu et al., 2010). In fact, an analysis of six studies with a total enrollment of 769 hearing impaired probands with EVA, a non-pathognomonic clinical finding that is a hallmark of PDS and DFNB4, reveals that only 25% have biallelic SLC26A4 mutations (Table 2). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pendred syndrome (PDS) and DFNB4 comprise a phenotypic spectrum of sensorineural hearing loss disorders that typically result from biallelic mutations of the SLC26A4 gene. Although PDS and DFNB4 are recessively inherited, sequencing of the coding regions and splice sites of SLC26A4 in individuals suspected to be affected with these conditions often fails to identify two mutations. We investigated the potential contribution of large SLC26A4 deletions and duplications to sensorineural hearing loss (SNHL) by screening 107 probands with one known SLC26A4 mutation by Multiplex Ligation-dependent Probe Amplification (MLPA). A heterozygous deletion, spanning exons 4-6, was detected in only one individual, accounting for approximately 1% of the missing mutations in our cohort. This low frequency is consistent with previously published MLPA results. We also examined the potential involvement of digenic inheritance in PDS/DFNB4 by sequencing the coding regions of FOXI1 and KCNJ10. Of the 29 probands who were sequenced, three carried nonsynonymous variants including one novel sequence change in FOXI1 and two polymorphisms in KCNJ10. We performed a review of prior studies and, in conjunction with our current data, conclude that the frequency of FOXI1 (1.4%) and KCNJ10 (3.6%) variants in PDS/DFNB4 individuals is low. Our results, in combination with previously published reports, indicate that large SLC26A4 deletions and duplications as well as mutations of FOXI1 and KCNJ10 play limited roles in the pathogenesis of SNHL and suggest that other genetic factors likely contribute to the phenotype.
    PeerJ 05/2014; 2(4):e384. DOI:10.7717/peerj.384 · 2.11 Impact Factor
  • Source
    • "It is also involved in the regulation of vascular H+-ATPase proton pumps in the inner ear, epididymis and kidney [30]. It was proposed that digenic inheritance of mutations in both FOXI1 and SLC26A4 were involved in the genetic basis of Pendred syndrome, as mutations in FOX1 were shown to reduce the transcription of SLC26A4[19]. Moreover, Foxi1 null mice showed phenotypic features of sensorineural deafness due to the defective pendrin-chloride mediated reabsorption in which FOXI1 was most likely a key regulator [29]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pendred syndrome is a common autosomal recessive disorder causing deafness. Features include sensorineural hearing impairment, goitre, enlarged vestibular aqueducts (EVA) and occasionally Mondini dysplasia. Hearing impairment and EVA may occur in the absence of goitre or thyroid dyshormonogensis in a condition known as non-syndromic EVA. A significant number of patients with Pendred syndrome and non-syndromic EVA show only one mutation in SLC26A4. Two genes, KCNJ10, encoding an inwardly rectifying potassium channel and FOXI1, a transcriptional factor gene, are thought to play a role in the disease phenotypes. Using Polymerase Chain Reaction and Sanger sequencing, sixty-eight patients with monoallelic mutations of SLC26A4 were tested for mutations in KCNJ10 and FOXI1. Two variants were observed in the KCNJ10 gene, p.Arg271Cys in three patients and p.Arg18Gln in one patient; only one variant, p.Arg123Trp was observed in the FOXI1 gene in a single patient. Both p.Arg271Cys and p.Arg18Gln are likely to be polymorphisms as judged by their frequency in the general population. Therefore we found no evidence for a significant association between mutations of KCNJ10 and FOXI1 with SLC26A4. It was also observed that the variant, p.Arg271Cys in KCNJ10, previously thought to have a protective effect against seizure susceptibility, was found in a patient with Pendred syndrome with co-existing epilepsy.
    BMC Medical Genetics 08/2013; 14(1):85. DOI:10.1186/1471-2350-14-85 · 2.08 Impact Factor
  • Source
    • "As with the GJB2 mutations, the pathogenic effects of some of the SLC26A4 changes haven’t been fully established and are controversial. This is the case for L597S [45], [46], [47], [48], [49], [50], [51], [52], IVS1-2A>G [51], and F335L [45]. PolyPhen-2 and SIFT Sequence predict the L597S and F335L changes are “probably damaging”, while SIFT BLink suggests they affect protein function (Table S4). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hearing loss is an etiologically heterogeneous trait with differences in the age of onset, severity and site of lesion. It is caused by a combination of genetic and/or environmental factors. A longitudinal study to examine the efficacy of early intervention for improving child outcomes is ongoing in Australia. To determine the cause of hearing loss in these children we undertook molecular testing of perinatal "Guthrie" blood spots of children whose hearing loss was either detected via newborn hearing screening or detected later in infancy. We analyzed the GJB2 and SLC26A4 genes for the presence of mutations, screened for the mitochondrial DNA (mtDNA) A1555G mutation, and screened for congenital CMV infection in DNA isolated from dried newborn blood spots. Results were obtained from 364 children. We established etiology for 60% of children. One or two known GJB2 mutations were present in 82 children. Twenty-four children had one or two known SLC26A4 mutations. GJB2 or SLC26A4 changes with unknown consequences on hearing were found in 32 children. The A1555G mutation was found in one child, and CMV infection was detected in 28 children. Auditory neuropathy spectrum disorder was confirmed in 26 children whose DNA evaluations were negative. A secondary objective was to investigate the relationship between etiology and audiological outcomes over the first 3 years of life. Regression analysis was used to investigate the relationship between hearing levels and etiology. Data analysis does not support the existence of differential effects of etiology on degree of hearing loss or on progressiveness of hearing loss.
    PLoS ONE 03/2013; 8(3):e59624. DOI:10.1371/journal.pone.0059624 · 3.23 Impact Factor
Show more


14 Reads
Available from