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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
Myosins are actin-based molecular motors that regulate several processes, such as the rearrangement of the actin cytoskeleton, the regulation of tension of actin filaments and the transport of organelles. Several mutations affecting the myosins are well identified (MYO3A, MYO6, MYO7A, and MYO15A for example). Most of the mutations in MYO7A cause Usher syndrome type I, an autosomal recessive genetic disorder characterized by congenital, bilateral, profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa. Usher syndrome represents about half of cases where both blindness and hearing impairments are present.
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
Usher syndrome (USH) is the most frequent autosomal recessive syndromic form of hearing loss. More than 50% of the deaf-blind community in the USA have USH. According to the genotype and phenotype differences, USH has several subtypes: Type I: congenital severe-to-profound sensorineural hearing loss, vestibular dysfunction and onset of retinitis pigmentosa in the first decade of lifeType II: mild-to-severe sensorineural hearing loss, normal vestibular function and onset of retinitis pigmentosa in the first or second decade of lifeType III: progressive hearing loss, progressive vestibular dysfunction and onset of retinitis pigmentosa is variable. To date 15 different loci and 12 genes have been reported (http://hereditaryhearingloss.org). One of these identified genes, MYO7A, encoding myosin 7A, is a unique molecular motor for hair cells.27 Cadherin 23, an adhesion molecule, coded by CDH23 gene may have an important role in cross linking of stereocilia.28
Autosomal Dominant Non-Syndromic Sensorineural Hearing Loss
Published in John C Watkinson, Raymond W Clarke, Christopher P Aldren, Doris-Eva Bamiou, Raymond W Clarke, Richard M Irving, Haytham Kubba, Shakeel R Saeed, Paediatrics, The Ear, Skull Base, 2018
Polona Le Quesne Stabej, Maria Bitner-Glindzicz
In 1992 the first AD SNHL locus (DFNA1) was mapped to chromosome 5q31 using linkage analysis in large multigenerational Costa Rican kindred. Five years later, in 1997, using laborious positional cloning as the human DNA sequence was not yet available, a splice mutation leading to a 4bp insertion in the mRNA and frameshift causing a truncating variant in DIAPH1gene was identified as the cause of AD SNHL in this family.7,8 Recently it has been shown that this leads to a constitutive activation of the encoded protein DIA1 by loss of autoinhibition.9 In the same year, it was shown that an in-frame 9-bp deletion in MYO7A and a truncating mutation in GJB2 were responsible for deafness in two families previously linked to DFNA11 and DFNA3A loci, respectively. Both genes were cloned after linkage analysis pointed to the two genes which were already known to cause autosomal recessive deafness.10–12 Linkage analysis followed by positional cloning and sequencing of candidate genes further led to identification of GJB3, DFNA5, COCH, POU4F3, TECTA, KCNQ4, TECTA, COL11A2 (see Table 58.1 for full list).13–19 Gene identification processes preceding the release of the human genome draft sequence in 200120 heavily relied on linkage analysis of large multigenerational families, bacterial artificial chromosome (BAC)-mediated cloning as well as singling out of candidate genes based on previous knowledge of gene function, mouse models or expression studies. In cases where no family members other than the proband were available, making linkage analysis impossible, a candidate gene approach was pursued (see Box 58.1). Examples of gene identification using the candidate gene approach are GJB6, CRYM and MYH14 genes, which were selected as candidate genes based on expression in the cochlea and vestibule, and data from existing mouse models coupled with the knowledge that genes from the same family have been previously shown to cause deafness. However, due to extreme heterogeneity of SNHL, sequencing of candidate genes in large groups of patients had a low yield, identifying deafness-causing variants in only 1/198 deaf families for GJB6, in 2/192 families for CRYM and in 4/300 families for MYH14.21–23 While the release of the human genome draft sequence in 2001 made targeted sequencing of candidate genes more straightforward, this approach is heavily biased as it relies on a priori knowledge of gene function and is therefore unlikely to reveal a novel deafness-causing gene or a novel pathway.
The applications of targeted delivery for gene therapies in hearing loss
Published in Journal of Drug Targeting, 2023
Melissa Jones, Bozica Kovacevic, Corina Mihaela Ionescu, Susbin Raj Wagle, Christina Quintas, Elaine Y. M. Wong, Momir Mikov, Armin Mooranian, Hani Al-Salami
Izumikawa et al. published a study which demonstrated the ability of Atoh1 to improve hearing thresholds via the regeneration of hair cells. The gene was administered utilising adenovirus vectors. Adult guinea pigs were deafened and had the transgene delivered to non-sensory cells of the left inner ear via infusion, four days following the ototoxic lesions. Various analyses were conducted, with results showing normal orientation and surface morphology to be observed in hair cells treated with Atoh1 adenovirus vectors, as well as determining that the hair cells expressed myo7a. In contrast, the untreated ears were found to be negative for myo7a. Overall, the results demonstrated a mixed phenotype of hair cell and supporting cell-like areas in the regenerated luminal surface of the auditory epithelium [122].
Investigation of MYO15A and MYO7A Mutations in Iranian Patients with Nonsyndromic Hearing Loss
Published in Fetal and Pediatric Pathology, 2021
Mahsa Farjami, Mozhgan Fathi, Mohammad Mehdi Ghasemi, Mohsen Rajati, Atieh Eslahi, Malihe Alimardani, Majid Mojarrad
MYO7A gene is located at 11q13.5 and codes for an unconventional myosin, which is expressed in the inner ear, lung, kidney, testis, and retina [10]. It is the first gene discovered that its mutations cause both syndromic (USH1B) and nonsyndromic (DFNB2, DFNA11) forms of hearing loss. HL due to MYO7A mutations can be inherited as an autosomal recessive (USH1B, DFNB2) or autosomal dominant (DFNA11) trait [11]. MYO7A p.R212H (c.635G > A; rs28934610) mutation is located in the conserved motor domain of myosin and was found for the first time in the Weston study, in 1995. It was reported as the most common MYO7A variant, comprising 31% of the mutations in Usher syndrome patients [12]. Another selected MYO7A mutation is p.R395H (c.1184G > A; rs387906700) at exon 11 of the MYO7A gene, which is located in the motor domain of the myosin. This substitution variant was first reported in a consanguineous Iranian family with nonsyndromic hearing loss (DFNB2) [13]. In 2015, it was shown to segregate in another Iranian family, who had severe to profound pre-lingual hearing loss [7]. Up to now, several mutations have been reported in this exon, like R395C in a Pakistani family and R397T in an Usher syndrome patient from USA [14,15].
Identification of a MYO7A mutation in a large Chinese DFNA11 family and genotype–phenotype review for DFNA11
Published in Acta Oto-Laryngologica, 2018
Lina Li, Hu Yuan, Hongyang Wang, Jing Guan, Lan Lan, Dayong Wang, Liang Zong, Qiong Liu, Bing Han, Deliang Huang, Qiuju Wang
In summary, clinical, genetic, and molecular characteristics of one large Chinese family with DFNA11 were reported. In addition, the pathogenic variant was identified using next-generation sequencing and the synergistic effects of other mutations that may cause high frequency hearing loss in Chinese populations at the same time were excluded. This study not only examined the clinical and genetic characteristics of the family, but also provided them with a basis for genetic counseling, especially for the members of the fifth or sixth generation. Furthermore, four of the nine DFNA11 families were from China, suggesting that MYO7A mutations are not rare. Therefore, we should pay more attention to Chinese patients with sporadic hearing loss that have excluded the possibility of common deafness mutations and develop a method of MYO7A mutational screening for them. Further functional studies of MYO7A gene mutations are required.