**Table 1.**

*Nonreceptor protein kinases and phosphatases implicated in hearing loss.*

*Nonreceptor Protein Kinases and Phosphatases Necessary for Auditory Function DOI: http://dx.doi.org/10.5772/intechopen.105425*

50% of all deafness cases, while the remaining is attributed to environmental factors such as exposure to loud noise, infections, or ototoxic drugs [4].

#### **1.3 Genes in hearing and deafness**

Genetic deafness can be monogenic in affected individuals or may have a more complex etiology. Many proteins orchestrate human hearing, and variants in hundreds of genes have been implicated in causing deafness. Some of these genes encode structural components within the auditory system; others encode proteins necessary for the function of the ear. Variants of many genes have been reported to cause structural defects of the ear with or without hearing loss in humans [4].

Inherited hearing loss has different modes of inheritance in different families [4]. These include autosomal dominant, autosomal recessive, X-linked, or mitochondrial inheritance. The autosomal forms are more commonly encountered as compared with the other types of inheritance patterns. Most of the dominantly inherited gene variants in humans cause postlingual, progressive, moderate to severe sensorineural hearing loss. In contrast, the majority of recessively inherited variants result in prelingual severe to profound sensorineural deafness [4]. However, exceptions exist for both dominant and recessive inherited hearing loss cases in which the phenotypic pattern for recessive forms resembles that of the dominant disorders or vice versa [5].

### **2. Protein kinases**

Hundreds of protein kinases are encoded in the human genome and constitute more than 2.5% of the coding genes [6]. These enzymes phosphorylate the hydroxyl groups of the target proteins at the serine/threonine residues (protein serine/threonine kinases) or act on the tyrosine residues (protein tyrosine kinases) or both (dual-specificity kinases). Generally, nonreceptor kinases are intracellular cytoplasmic or nuclear proteins. Variants of most of these genes cause hearing loss in only a subset of the affected individuals, suggesting a degree of redundancy for the function of the auditory system. One such gene is *CASK*; patients with C*ASK* variants have an Intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia syndrome, and only a few individuals also have a hearing loss [7]. Interestingly, CASK has been shown to interact with whirlin and prestin in the inner ear; [8, 9] two proteins that are vital to hearing.

Sometimes, hearing loss phenotype is not investigated or observed in mouse models for many of the genes, which are known to cause deafness in humans. In other cases, targeted disruption of a gene, for example, *Cdk5*, causes lethality in mice, necessitating the development of animal models with selective deletion of the gene of interest in the inner ear [10] in order to determine the effect of the absence of the protein in the auditory system. Multiple studies on mouse models with deafness have suggested that some of the kinases important for hearing have roles in the kinocilia formation or maintenance of the stereocilia [9].

#### **2.1 Dual-specificity kinases**

DYRK1A is a dual-specificity kinase, which has been implicated in individuals with mental retardation and outer ear morphological defects (**Table 1**). Some individuals also experience hearing loss due to *DYRK1A* variants [11]. DYRK1A

autophosphorylates itself at both serine/threonine and tyrosine residues, and thus controls its own activity. Another dual-specificity kinase, MAP2K1 is required for activation of MAPK by phosphorylating both serine and tyrosine residues. Variants of *MAP2K1* have been associated with hearing loss in a few patients diagnosed with either of two different human syndromes (**Table 1**), as an accompanying feature to the cardiovascular defects [12, 13].

#### **2.2 Protein serine/threonine kinases**

Protein serine/threonine kinases are the most frequent types of kinases that have been implicated to have a role in hearing (**Table 1**). Variants of all member genes of this group, except for *MYO3A*, cause syndromic deafness in humans (**Table 1**). In some instances, hearing loss is accompanied by ear malformations, as is the case in patients with frontometaphyseal dysplasia 2. Frontometaphyseal dysplasia 2 is caused due to variants affecting MAP3K7, and conductive or sensorineural deafness is accompanied by ear malformations [14]. For a vast majority of protein serine/ threonine kinases, such as CDC42BPB, CDK8, CDK9, CDK10, CDK13, the association of hearing loss due to variants of the genes in the corresponding syndromes is based on the presence of the auditory phenotype in one or only a few individuals [15–19]. Therefore, some of these genetic variants links to human auditory malfunction may prove to be coincidental.

In a few cases, only particular types of variants of a gene may be associated with hearing loss. For example, patients with a heterozygous nonsense variant of *PRKCG* have spinocerebellar ataxia 14 with hearing loss, while patients with missense variants do not have an auditory phenotype [20]. In other instances, many individuals may be affected by hearing loss, but these only constitute up to 30% of the total patients reported to have a particular syndrome due to the corresponding gene variants. For example, Coffin-Lowry Syndrome is a disorder in which patients have mental retardation, skeletal defects, and movement disorders with or without hearing loss. It is caused as a result of *RPS6KA3* variants [21].

The variants of *MAPKAPK5* [22], *PRKCB* [23], and *BRAF* [24] have been reported to cause hearing loss in humans, but not in mice. Variants of some protein serine/threonine kinases such as *RAF1* [25] and *MAP3K20* [26] cause hearing loss in humans, and their orthologous genes have a demonstrated role in mouse audition as well [26, 27]. In other cases, importance of a gene to mammalian hearing can only be gauged due to the observed phenotype in mouse models. For example, pathogenic alleles of *Map3k1* [28, 29], *Map3k4* [30], *Pak1* [31], and *Stk11* [32] are reported to cause hearing loss in mice only. Mice with *Mapk1* deletion in the inner ear undergo noise-induced hearing loss [33]. However, deafness has not been reported as yet in humans, but patients with *MAPK1* variants have outer ear morphological defects [34].

An interesting example of a protein serine/threonine kinase is MYO3A since it has both a C-terminal motor domain and an N-terminal kinase domain. Its loss of function variants usually cause recessively inherited moderate to severe nonsyndromic hearing loss, which can be adult onset and progressive in nature [5]. One homozygous variant abolishes MYO3A kinase function, and the affected individuals have profound deafness [35]. Dominantly inherited *MYO3A* variants are very rare. Of the latter, a heterozygous missense variant affecting the kinase domain was reported to cause hearing loss in affected individuals of a German family [36]. The MYO3A kinase activity may be important for phosphorylation of its own motor domain, thus reducing motor activity and regulating protein concentration in the stereocilia [37].

Different mice models homozygous for a knock-in nonsense variant or a missense variant in the kinase domain have progressive hearing loss [38, 39], mimicking the phenotype observed in humans.
