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Genomics and Hearing Loss: Toward a New Standard of Care?
Published in Stavros Hatzopoulos, Andrea Ciorba, Mark Krumm, Advances in Audiology and Hearing Science, 2020
Transmembrane anion exchanger: The SLC26A4 gene encodes the pendrin protein, a transmembrane anion exchanger and is expressed in different tissues, including the thyroid, kidney and inner ear. Mutations in the pendrin gene are the second most frequent cause of autosomal recessive nonsyndromic hearing loss, accounting for up to 3.5% of cases (Hutchin et al., 2005). SLC26A4 also underlies Pendred syndrome, which is one of the most common autosomal recessive syndromic causes of hearing loss. In humans, enlargement of the vestibular aqueduct is present in almost all individuals with Pendred syndrome or DFNB4 deafness although an enlarged vestibular aqueduct can be present as an isolated finding along with sensorineural hearing loss. Mutations in SLC26A4 cause a spectrum of hearing loss, congenital or with a late onset, ranging from mild to profound, stable or progressive along the lifetime. Approximately half of the Pendred syndrome cases are caused by a mutation in SLC26A4.
Pendred Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The SLC26A4 (solute carrier family 26 member 4, or human pendrin polypeptide) gene on chromosome 7q22.3 spans 67 kb and encodes a 780 aa, 85 kDa anion transporter protein (pendrin) belonging to the SLC26 anion transporter family.
Genetics in Otology and Neurotology
Published in John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie, Basic Sciences Endocrine Surgery Rhinology, 2018
This is the second most common type of autosomal recessive syndromic hearing loss. It is usually characterized by severe congenital sensorineural hearing loss and euthyroid goitre that develops in puberty or adulthood. The deafness is also commonly associated with an abnormality of the labyrinth which may be anatomical (Mondini dysplasia or dilated vestibular aqueduct) and/or functional. Almost 50% of the families have SLC26A4 (PDS) gene mutation on chromosome 7q21-q34. The gene is responsible for sulfate transport. Its protein product, pendrin, is involved in the transport of iodine and chloride ions. SLC26A4 gene mutation should be investigated in the patients who have progressive hearing loss, Mondini dysplasia or large vestibular aqueduct syndrome. The same mutation can also cause DFNB4.29
Cochlear implantation in the era of genomic medicine
Published in Cochlear Implants International, 2020
Leslie P. Molina-Ramirez, Iain A. Bruce, Graeme C. M. Black
When inexorable progression in hearing loss is anticipated based on genotype, it is yet to be determined whether an ‘early’ or ‘pre-emptive’ CI with attempted hearing preservation is better functionally and emotionally than waiting until conventional hearing aids no longer provide benefit. Likewise, correlating genotype with other clinical, radiological or patient characteristics may provide important information about anticipated deterioration in preserved natural hearing after CI. For instance, several studies have explored the relationship between mutations in the gene SLC26A4 and the presence of enlarged vestibular aqueducts (EVA) and cochlear dysplasia (King et al., 2009). Thus far, there remains a lack of consistency in the association between the impact of the mutated protein, radiological findings and hearing loss severity (Chattaraj et al., 2013; Liu et al., 2016; Okamoto et al., 2014; Zhao et al., 2013), particularly in those cases where no mutations in SLC26A4 are identified (Pryor et al., 2005). Expanding the analysis using genomic sequencing could investigate other potential molecular genetic mechanisms involved in the development of cochleovestibular anomalies, which may have applications for electrode or device selection (Table 1).
A pathogenic variant in SLC26A4 is associated with Pendred syndrome in a consanguineous Iranian family
Published in International Journal of Audiology, 2019
Azam Pourahmadiyan, Paria Alipour, Najmeh Fattahi, Mahbubeh Kasiri, Fateme Rezaeian, Afsaneh Taghipour-Sheshdeh, Javad Mohammadi-Asl, Mohammad Amin Tabatabaiefar, Morteza Hashemzadeh Chaleshtori
The variant, p.Thr404Ile, is located in the tenth transmembrane (TM) domain of the pendrin protein. In a model with 14 TM domains, the clusters of pathogenic variants were found in TM3, TM10, and at the C-terminus of TM11. These variants are suspected to promote disease onset by affecting anion transport between TM3 and TM10, two fundamental regions for the SLC26 protein family (Gorbunov et al. 2014; Geertsma et al. 2015). Specifically for SLC26A4, TM3 and TM10, as well as the SulP and Saier motifs, are involved in pendrin anion transport (Bassot et al. 2017). Of note, 35% of PDS-causative variants are localised within TM3 and TM10, emphasising that both regions are functionally relevant for pendrin activity. Moreover, the variant found in this study is rather conserved among different species, including five classes of vertebrates. Intriguingly, the residue is a serine in the zebra fish, suggesting that the OH group of serine and threonine might play a role in the function of the protein. Besides, the aforementioned variant is facing towards the protein interior, similar to other pathogenic variants. Importantly, a mutated residue has more pathological effect when altering the protein core than when contacting lipids. Essentially, lipid facing variants promote changes in solvation energy and have a disruptive effect on hydrophobic interactions with the lipid bilayer (Rotman-Pikielny et al. 2002; Taylor et al. 2002; Bassot et al. 2017).
Mutation spectrum and hotspots of the common deafness genes in 314 patients with nonsyndromic hearing loss in Heze area, China
Published in Acta Oto-Laryngologica, 2019
Meng Zhang, Yuechen Han, Fengguo Zhang, Xiaohui Bai, Haibo Wang
A total of 68 patients (21.66%, 68/314) carried the SLC26A4 mutation gene and 48 patients among them (15.29%, 48/314) carried more than one pathological mutations. Furthermore, previous surveys carried out in different China regions showed that the mutant carrier rate of SCL26A4 were 7.04% (82/1164) in Southwestern China [13], 15.2% (78/514) in Northern China [14] and 9.52% (4/42) in minority patients and 9.84% (19/193) of Han Chinese patients in Yunnan China [15]. According to our results, the mutant carrier rate of SCL26A4 gene in Heze area was significantly different with Southwestern China region (p = .000), Yunnan China region (Han Chinese patients; p = .001) and the Northern China region (p = .018). Thus, our results disclosed the special and unique status of SLC26A4 mutation in Heze deafness population.