Sensorineural hearing loss associated with enlargement of the vestibular aqueduct (EVA) can be associated with mutations of the SLC26A4 gene. In western populations, less than one-half of the affected individuals with EVA have two mutant SLC26A4 alleles, and EVA is frequently caused by unknown genetic or environmental factors alone or in combination with a single SLC26A4 mutation as part of a complex trait. In this study, we ascertained 26 Korean probands with EVA and performed nucleotide sequence analysis to detect SLC26A4 mutations. All subjects had bilateral EVA, and 20 of 26 were sporadic (simplex) cases. Fourteen different mutations were identified, including nine novel mutations. Five mutations were recurrent and accounted for 80% of all mutant alleles, providing a basis for the design and interpretation of cost-efficient mutation detection algorithms. Two mutant alleles were identified in 21 (81%), one mutant allele was detected in three (11%), and zero mutant allele was detected in two (8%) of 26 probands. The high proportion of Korean probands with two SLC26A4 mutations may reflect a reduced frequency of other genetic or environmental factors causing EVA in comparison to western populations.
-M., Crook, J. M., de Sousa, P. A. et al (2015). Points to consider in the development of seed stocks of pluripotent stem cells for clinical applications: International Stem Cell Banking Initiative (ISCBI). Regenerative Medicine, 10 (2s), 1-44.
These results indicate that the processing of pendrin mutant protein is determined by mutant specific mechanisms, and that a mutant specific method would be required to rescue the conformational defects of each folding mutant.
Vertebrate hearing and balance are based in complex asymmetries of inner ear structure. Here, we identify retinoic acid (RA) as an extrinsic signal that acts directly on the ear rudiment to affect its compartmentalization along the anterior-posterior axis. A rostrocaudal wave of RA activity, generated by tissues surrounding the nascent ear, induces distinct responses from anterior and posterior halves of the inner ear rudiment. Prolonged response to RA by posterior otic tissue correlates with Tbx1 transcription and formation of mostly nonsensory inner ear structures. By contrast, anterior otic tissue displays only a brief response to RA and forms neuronal elements and most sensory structures of the inner ear.axial specification | developmental compartments | morphogen N ormal hearing and balance require that discrete patches of mechanosensory hair cells, each with a distinct function, be precisely positioned within the asymmetric membranous labyrinth of the inner ear (Fig. 1A). Five vestibular sensory patches are present in all vertebrate inner ears: the three cristae (anterior, lateral, and posterior) that detect angular head movements and two maculae (utricle and saccule) that detect linear acceleration. The specialized organ for detecting sound in chickens and mammals is the basilar papilla and organ of Corti, respectively.The entire membranous labyrinth and its innervating neurons are derived from an ectodermal thickening adjacent to the hindbrain known as the otic placode. As the placode deepens to form a cup and then pinches off to form the otocyst, some cells of the otic epithelium delaminate to form neuroblasts of the cochleovestibular ganglion (CVG). Inner ear sensory organs, and the neurons that innervate them, are thought to arise from a neural-sensory competent domain (NSD), most of which is located in the anterior region of the otic cup (1). By contrast, posterior otic epithelium forms nonsensory tissues and only one sensory organ, the posterior crista. This basic organization of functional elements in the ear is thought to be governed by signals emanating from adjacent tissues (2, 3); however, molecular mechanisms that establish the initial anterior-posterior (A-P) asymmetry of the ear primordium are poorly defined. Here, we show that a rostrocaudal wave of retinoic acid activity provides signals to the ear rudiment and establishes structural asymmetries required for normal hearing and balance. ResultsEctoderm Adjacent to the Otic Cup Confers A-P Polarity to the Otocyst. A clear manifestation of A-P asymmetry in developing amniote ears is the anterior expression of transcripts associated with cochleovestibular ganglion neurogenesis. We performed tissue transplantations in ovo to identify source(s) of signals that specify the otic A-P axis in the chicken. Transplantations were carried out at the otic cup stage (11-15 somite stages), before the otic A-P axis is specified (4). As expected, reversing the A-P orientation of the otic cup alone resulted in a high occurrence of otocysts with the axial plan...
Lmx1a is a LIM homeodomain-containing transcription factor, which is required for the formation of multiple organs. Lmx1a is broadly expressed in early stages of the developing inner ear, but its expression is soon restricted to the non-sensory regions of the developing ear. In an Lmx1a functional null mutant, dreher (drJ/drJ), the inner ears lack a non-sensory structure, the endolymphatic duct, and the membranous labyrinth is poorly developed. These phenotypes are consistent with Lmx1a’s role as a selector gene. More importantly, while all three primary fates of the inner ear – neural, sensory, and non-sensory – are specified in drJ/drJ, normal boundaries among these tissues are often violated. For example, the neurogenic domain of the ear epithelium, from which cells delaminate to form the cochleovestibular ganglion, is expanded. Within the neurogenic domain, the demarcation between the vestibular and auditory neurogenic domains is most likely disrupted as well, based on the increased numbers of vestibular neuroblasts and ectopic expression of Fgf3, which normally is associated specifically with the vestibular neurogenic region. Furthermore, aberrant and ectopic sensory organs are observed; most striking among these is vestibular-like hair cells located in the cochlear duct.
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