**3.1 Atypical protein phosphatases**

The atypical protein phosphatases have an N-terminal threonine phosphatase and a C-terminal tyrosine phosphatase domain [44]. EYA1 and EYA4 are two atypical protein phosphatases that are important for hearing. Variants of *EYA1* cause two allelic syndromes in humans, which include hearing loss as one of the manifestations, along with multiple outer and inner ear structural defects [46, 47]. Homozygous *Eya1* mutant mice lack ears, which suggest an essential role of the encoded protein in early development [48]. Similarly, EYA4 is essential for maintenance of hearing in humans [49, 50] and mice [51]. EYA4 is one of the very few phosphatases, variants of which cause nonsyndromic deafness in humans [49], although some of its variants also give rise to a syndromic form of deafness with dilated cardiomyopathy [50].

## **3.2 Dual-specificity phosphatases**

Dual-specificity phosphatases can catalyze the removal of phosphates from both phosphorylated tyrosine and serine/threonine residues of the target proteins. They are structurally similar to the tyrosine phosphatase family enzymes. CDC14A is a dual-specificity phosphatase and has been shown to be absolutely necessary for hearing in both humans [52, 53] and mice [53]. Moreover, some variants cause hearing loss with immotile sperm in humans and mice [53]. Most phospho protein targets of CDC14A are unknown, though drebrin (DBE1) has been proposed to be one such protein [54]. Two other dual-specificity phosphatases, DUSP1 [55, 56] and DUSP6 [57], are important for hearing in mice. *Dusp1* knockout mouse mutants manifest a progressive hearing loss [56], perhaps due to disruption of cytokines [55]. Similarly, DUSP6 is required for ear development in mice [58]. Few patients with hypogonadotropic hypogonadism 19 with or without anosmia may have a hearing loss due to *DUSP6* variants [59].

One unusual dual-specific protein phosphatase is PTEN, which has both lipid phosphatase and dual-specific protein phosphatase activities. Although lipid dephosphorylation by PTEN is well studied, that of protein dephosphorylation is less so. However, it was shown that PTEN plays a role in ciliogenesis by phosphorylating the protein DVL2 [60]. Heterozygous knockout *Pten*+/− mice have inner ear abnormalities [61] while the inner ear specific homozygous knockout mice are deaf [62] and have supernumerary hair cells [63]. In humans, some patients with Cowden syndrome have a hearing loss due to *PTEN* variants [64].

### **3.3 Protein tyrosine phosphatases nonreceptor type**

Variants of protein tyrosine phosphatase PTPN11 cause two autosomal dominant syndromes (**Table 1**) in which patients can have hearing loss with multiple other disorders including cardiovascular manifestations [65, 66]. Sometimes, hearing loss is presented as the first symptom of the syndrome [67], while other individuals exhibit only the auditory phenotype as a nonsyndromic case [68]. Studies in HEK293 cells have demonstrated that PTPN11 variants involved in human disorders affect dephosphorylation of GAB1 [69]; another protein that is important for hearing [70].
