Otoancorin, an inner ear protein restricted to the interface between the apical surface of sensory epithelia and their overlying acellular gels, is defective in autosomal recessive deafness DFNB22

Abstract

A 3,673-bp murine cDNA predicted to encode a glycosylphosphatidylinositol-anchored protein of 1,088 amino acids was isolated during a study aimed at identifying transcripts specifically expressed in the inner ear. This inner ear-specific protein, otoancorin, shares weak homology with megakaryocyte potentiating factor͞ mesothelin precursor. Otoancorin is located at the interface between the apical surface of the inner ear sensory epithelia and their overlying acellular gels. In the cochlea, otoancorin is detected at two attachment zones of the tectorial membrane, a permanent one along the top of the spiral limbus and a transient one on the surface of the developing greater epithelial ridge. In the vestibule, otoancorin is present on the apical surface of nonsensory cells, where they contact the otoconial membranes and cupulae. The identification of the mutation (IVS12؉2T>C) in the corresponding gene OTOA in one consanguineous Palestinian family affected by nonsyndromic recessive deafness DFNB22 assigns an essential function to otoancorin. We propose that otoancorin ensures the attachment of the inner ear acellular gels to the apical surface of the underlying nonsensory cells. T he mammalian inner ear consists of the cochlea, the organ of hearing, and the vestibule, which is responsible for balance. The vestibule is composed of five separate organs, the saccule, the utricle, and three cristae of the semicircular canals. The apical surface of each sensory organ is covered by an acellular gel. The tectorial membrane (TM) lies over the surface of the organ of Corti in the cochlea, an otoconial membrane covers the macula of the utricle and saccule, and a cupula sits on top of each crista in the ampullae of the semicircular canals. Relative motion generated between the apical surface of the sensory epithelium and the overlying acellular gel, in response to sound-induced basilar membrane motion in the cochlea or head motion in the vestibule, results in deflection of the hair cell's stereociliary bundle, thereby modulating the gating of mechanotransducer channels.With the exception of prestin (1), all of the inner ear-specific proteins described so far in mammals, namely ␣-and ␤-tectorin (2), otogelin (3), and otoconin-95 (4), are components of these acellular gels. In the mouse inner ear, ␣-and ␤-tectorin are components of the tectorial and otoconial membranes but are not present in the cupulae (2). Otogelin is present in all of the acellular gels (3). Otoconin-95 is the major component of the otoconia, dense biominerals that load the otoconial membrane and provide inertial mass (4, 5), and is also present in the cupulae. The mammalian TM is a complex structure composed of collagen fibrils imbedded in a collagenase-insensitive striated-sheet matrix (6). Otogelin is associated mainly with the collagen fibril bundles (3, 7), whereas ␣-and ␤-tectorin are major components of the striated-sheet matrix (8, 9). Collagens are not prominent components of either the otoconial membranes or cupulae. Thus far, little is known about ...

Differential Expression of Genes within the Cochlea as Defined by a Custom Mouse Inner Ear Microarray

“…This microarray increases our chances of finding new or novel genes involved in hearing or in development of the ear. As demonstrated in this study, four differentially expressed genes, Otoa, Otor, Otos, and Tmprss3, were identified that are associated with hearing impairment ( Zwaenepoel et al 2002). Although a number of unidentified singletons exhibited differential expression in the LW, OC, or SG, none were found to colocalize with a deafness locus Pompeia et al 2004).…”

“…(Otoa) and transmembrane serine protease 3 (Tmprss3), which are both implicated in autosomal recessive deafness Zwaenepoel et al 2002). Also included are otoraplin (Otor), a possible deafness gene associated with the otic capsule (Cohen-Salmon et al 2000), and otospiralin (Otos), which leads to hair cell degeneration and deafness in guinea pigs when downregulated (Delprat et al 2002).…”

Scleraxis is Required for Differentiation of the Stapedius and Tensor Tympani Tendons of the Middle Ear

“…Scx is expressed in interdental cells of the spiral limbus that produce otoanchorin which is defective in nonsyndromic, autosomal recessive deafness, DFNB22 (Zwaenepoel et al 2002). Scx is found in mechanically sensitive hair cells that transduce sound energy into electrical signals that subserve hearing (Hudspeth 1997).…”

“…Molecular defects in interdental cells, hair cells, or supporting cells in the organ of Corti are associated with auditory dysfunction (Zwaenepoel et al 2002;Zhu and Zhao 2010). Since Scx is expressed in all of these cell types, we measured auditory thresholds in Scx-null and control Scx-GFP mice.…”

Haplotypes in the gene encoding protein kinase c-beta (PRKCB1) on chromosome 16 are associated with autism

“…The OTOA gene is not expressed in the brain but solely in the inner ear at the interface between the apical surface and the inner ear sensory epithelia. 72 The gene was first cloned in 2002 and it was shown that a disruptive, recessive splice site mutation in the gene lead to deafness in a large Palestinian family. 72 Affected members of the family presented a moderate to severe prelingual deafness.…”