Search

Abstract Background Treacher Collins syndrome (TCS; OMIM 154500) is a craniofacial developmental disorder. Methods To investigate the genetic features of a four-generation Chinese family with TCS, clinical examinations, hearing tests, computed tomography, whole-exome sequencing (WES), Sanger sequencing, reverse transcription (RT)-PCR, and the Minigene assay were performed. Results The probands, an 11-year-old male and his cousin exhibited typical clinical manifestations of TCS including conductive hearing loss, downward slanting palpebral fissures, and mandibular hypoplasia. Computed tomography revealed bilateral fusion of the anterior and posterior stapedial crura and malformation of the long crura of the incus. WES of both patients revealed a novel heterozygous intronic variant, i.e., c.4342 + 5_4342 + 8delGTGA (NM_001371623.1) in TCOF1. Minigene expression analysis revealed that the c.4342 + 5_4342 + 8delGTGA variant in TCOF1 caused a partial deletion of exon 24 (c.4115_4342del: p.Gly1373_Arg1448del), which was predicted to yield a truncated protein. The deletion was further confirmed via RT-PCR and sequencing of DNA from proband blood cells. A heterozygous variant in the POLR1C gene (NM_203290; exon6; c.525delG) was found almost co-segregated with the TCOF1 pathogenic variant. Conclusions In conclusion, we identified a heterozygous TCOF1 splicing variant c.4342 + 5_4342 + 8delGTGA (splicing) in a Chinese TSC family with ossicular chain malformations and facial anomalies. Our findings broadened the spectrum of TCS variants and will facilitate diagnostics and prognostic predictions.

Dentin matrix protein 1 (Dmp1) is a highly phosphorylated, extracellular matrix protein that is extensively expressed in bone and teeth but also found in soft tissues, including brain and muscle. However, the functions of Dmp1 in the mice cochlea are unknown. Our study showed that Dmp1 was expressed in auditory hair cells (HCs), with the role of Dmp1 in those cells identified using Dmp1 cKD mice. Immunostaining and scanning electron microscopy of the cochlea at P1 revealed that Dmp1 deficiency in mice resulted in an abnormal stereociliary bundle morphology and the mispositioning of the kinocilium. The following experiments further demonstrated that the cell-intrinsic polarity of HCs was affected without apparent effect on the tissue planer polarity, based on the observation that the asymmetric distribution of Vangl2 was unchanged whereas the Gαi3 expression domain was enlarged and Par6b expression was slightly altered. Then, the possible molecular mechanisms of Dmp1 involvement in inner ear development were explored via RNA-seq analysis. The study suggested that the Fgf23–Klotho endocrine axis may play a novel role in the inner ear and Dmp1 may regulate the kinocilium–stereocilia interaction via Fgf23–Klotho signaling. Together, our results proved the critical role of Dmp1 in the precise regulation of hair bundle morphogenesis in the early development of HCs.

As part of the inner ear, the vestibular system is responsible for sense of balance, which consists of three semicircular canals, the utricle, and the saccule. Increasing evidence has indicated that the noncanonical Wnt/PCP signaling pathway plays a significant role in the development of the polarity of the inner ear. However, the role of canonical Wnt signaling in the polarity of the vestibule is still not completely clear. In this study, we found that canonical Wnt pathway-related genes are expressed in the early stage of development of the utricle and change dynamically. We conditionally knocked out β-catenin, a canonical Wnt signaling core protein, and found that the cilia orientation of hair cells was disordered with reduced number of hair cells in the utricle. Moreover, regulating the canonical Wnt pathway (Licl and IWP2) in vitro also affected hair cell polarity and indicated that Axin2 may be important in this process. In conclusion, our results not only confirm that the regulation of canonical Wnt signaling affects the number of hair cells in the utricle but also provide evidence for its role in polarity development.

Objectives: This study compared the rate of graft success, as well as hearing improvement and dry ear time between dry ears and wet ears with otomycosis or without otomycosis in patients with chronic suppurative otitis media (CSOM) after endoscopic cartilage myringoplasty. Methods: This retrospective study was conducted in a tertiary hospital in Shanghai. In total, 83 patients with CSOM (43 with dry ears and 40 with wet ears) were included. Among the 40 patients with CSOM and wet ears, 25 exhibited otomycosis. All patients underwent endoscopic myringoplasty, and perforations were repaired using tragal cartilage with a singlesided perichondrium. Patients were followed up for at least 6 months. Pure-tone hearing was examined preoperatively and at 3 months postoperatively. The graft uptake rate, hearing improvement, and dry ear time were compared between the groups. Results: The graft success rate did not differ significantly between the dry-ear and wet-ear groups (95.35% and 90.00%, respectively). Furthermore, the graft success rate also did not differ significantly between patients with wet ears and otomycosis and those with wet ears without otomycosis (92.00% and 86.67%, respectively). Hearing gain did not differ significantly between the dry-ear and wet-ear groups. No significant difference in hearing gain was also found in patients with wet ears with or without otomycosis. However, the time to dry ear was significantly longer in the wet-ear group than in the dry-ear group. Conclusion: Patients with CSOM and wet ears required more time to achieve a completely healthy status. However, the graft success rate and hearing improvement were not affected by a wet middle ear and otomycosis. Thus, endoscopic myringoplasty using tragus cartilage is an effective treatment for refractory CSOM in patients with wet ears and otomycosis. [ABSTRACT FROM AUTHOR]