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: 10.99). 07/2007; 80(6):1055-63. DOI: 10.1086/518314
Source: PubMed

ABSTRACT 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.

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    • "c o m / l o c a t e / i j p o r l example, the FOXI1 (5q34) gene encodes for a transcriptional activator that is required to develop normal hearing, sense of balance and kidney function. This activator allows the transcription of the SLC26A4 gene [16]. Furthermore, mutations in the inwardly rectifying K(+) channel gene KCNJ10 (1q23.2) are also associated with non syndromic hearing loss in carriers of SLC26A4 mutations with an EVA/PS phenotype [17]. "
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    ABSTRACT: Mutations in the SLC26A4 gene (7q22.3-7q31.1) are considered one of the most common causes of genetic hearing loss. There are two clinical forms related to these mutations: syndromic and non-syndromic deafness. The first one is named Pendred Syndrome (PS) when deafness is associated with thyroid goiter; the second is called DFNB4, when no other symptoms are present. Both are transmitted as an autosomal recessive trait, but simple heterozygotes can develop both forms of deafness. Actually it is thought that Pendred Syndrome occurs when both alleles of SLC26A4 gene are mutated; DFNB4 seems due to monoallelic mutations. PS and DFNB4 can be associated with inner ear malformations. In most of the cases (around 80%), these consist in Enlarged Vestibular Aqueduct (EVA). EVA can also be present without SLC26A4 mutations. Understanding the role of new SLC26A4 variants should facilitate clinical assessment, as well as diagnostic and therapeutic approaches. This investigation aims to detect and report genetic causes of two unrelated Italian boys with hearing loss. Patients and family members underwent clinical, audiological and genetic evaluations. To identify genetic mutations, DNA sequencing of SLC26A4 gene (including all 21 exons, exon-intron boundaries and promoter region) was carried out. Both probands were affected by congenital, progressive and fluctuating mixed hearing loss. Temporal bone imaging revealed a bilateral EVA with no other abnormalities in both cases. Probands were heterozygotes for previously undescribed mutations in the SLC26A4 gene: R409H/IVS2+1delG (proband 1) and L236P/K590X (proband 2). No other mutations were detected in GJB2, GJB6 genes or mitochondrial DNA (mit-DNA). The IVS2+1delG and K590X mutations have not yet been described in literature but there is some evidence to suggest that they have a pathological role. The results underlined the importance of considering the complete DNA sequencing of the SLC26A4 gene for differential molecular diagnosis of deafness, especially in those patients affected by congenital, progressive and fluctuating mixed hearing loss with bilateral EVA.
    International journal of pediatric otorhinolaryngology 06/2012; 76(9):1249-54. DOI:10.1016/j.ijporl.2012.05.014 · 1.32 Impact Factor
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    • "SLC26A4's transcriptional regulating factor, FOXI1, and SLC26A4's functional partner KCNJ10 have also been implicated in the development of inner ear abnormalities [13] [14]. FOXI1 mutations were observed in Pendred syndrome and non-syndromic EVA patients by Yang et al. [13]. In the study, they described five Pendred syndrome or non-syndromic EVA patients carrying a heterozygous FOXI1 mutation. "
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    ABSTRACT: To investigate the implication of SLC26A4, FOXI and KCNJ10 genes in unilateral hearing impairment associated with ipsilateral inner ear malformation (Enlargement of the vestibular aqueduct and/or Mondini dysplasia). We have gathered 25 patients presenting unilateral hearing impairment and ipsilateral enlarged vestibular aqueduct. For each of the patients, we have analyzed SLC26A4, FOXI1 and KCNJ10 genes sequences. The analysis of SLC26A4 revealed only eight heterozygous SLC26A4 sequence variants, three of them being novel (p.Met147Ile, p.Asn538Asn and p.Leu627Arg). None of the patients carried a second mutation on the other allele. Moreover, the SLC26A4 locus was excluded by segregation analysis in two families. No mutations were present in FOXI1 and KCNJ10 genes. Together, these data suggest that SLC26A4, FOXI1 and KCNJ10 are not major determinants in unilateral deafness and enlarged vestibular aqueduct compared with their implication in Pendred syndrome and non-syndromic bilateral enlarged vestibular aqueduct.
    International journal of pediatric otorhinolaryngology 09/2010; 74(9):1049-53. DOI:10.1016/j.ijporl.2010.06.002 · 1.32 Impact Factor
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    ABSTRACT: Seventeen unrelated Danish patients with Pendred's syndrome, whose case stories have not been published previously, are presented. Acoustic and vestibular functions were examined and endocrinological screening was performed. There was a great variation in hearing ability as well as in thyroid function. Furthermore, in contrast to previous investigations, normal caloric function was demonstrated in the majority. In all patients a Mondini malformation was demonstrated. On the basis of this investigation it is concluded that: (1) the Mondini defect is part of Pendred's syndrome; (2) the inherited Mondini malformation is the underlying cause of the sensorineural hearing impairment; and (3) the hearing sensitivity varies greatly in these patients.
    The Journal of Laryngology & Otology 10/1987; 101(11):1187 - 1192. DOI:10.1017/S0022215100103470 · 0.70 Impact Factor
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