Target sequencing of 307 deafness genes identifies candidate genes implicated in microtia

Wang, Pu; Fan, Xinmiao; Wang, Yibei; Fan, Yue; Liu, Yaping; Zhang, Shuyang; Chen, Xiaowei

doi:10.18632/oncotarget.18803

Cited by 11 publications

(15 citation statements)

References 26 publications

(32 reference statements)

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“…Furthermore, GALR1 and WDR45 loci identified in the present study have been linked to congenital developmental auditory dysfunction. A large mutation screening of 307 deafness genes in patients with microtia identified GALR1 as a strong candidate gene (amongst others) with novel mutations associated with microtia (62). Microtia is a malformation of the external ear that ranges in severity from mild differences in auricular shape and size to complete absence of the external ear with atresia or stenosis of the auditory canal that may be caused by genetic and/or environmental factors (63,64).…”

Section: Tinnitusmentioning

confidence: 99%

DNA Methylation Patterns of Chronic Explosive Breaching in U.S. Military Warfighters

Wang

Wilson

et al. 2020

Front. Neurol.

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Background: Injuries from exposure to explosions rose dramatically during the Iraq and Afghanistan wars, which motivated investigation of blast-related neurotrauma. We have undertaken human studies involving military "breachers"-exposed to controlled, low-level blast during a 3-days explosive breaching course. Methods: We screened epigenetic profiles in peripheral blood samples from 59 subjects (in two separate U.S. Military training sessions) using Infinium MethylationEPIC BeadChips. Participants had varying numbers of exposures to blast over their military careers (empirically defined as high ≥ 40, and conversely, low < 39 breaching exposures). Daily self-reported physiological symptoms were recorded. Tinnitus, memory problems, headaches, and sleep disturbances are most frequently reported. Results: We identified 14 significantly differentially methylated regions (DMRs) within genes associated with cumulative blast exposure in participants with high relative to low cumulative blast exposure. Notably, NTSR1 and SPON1 were significantly differentially methylated in high relative to low blast exposed groups, suggesting that sleep dysregulation may be altered in response to chronic cumulative blast exposure. In comparing lifetime blast exposure at baseline (prior to exposure in current training), and top associated symptoms, we identified significant DMRs associated with tinnitus, sleep difficulties, and headache. Notably, we identified KCNN3, SOD3, MUC4, GALR1, and WDR45B, which are implicated in auditory function, as differentially methylated associated with self-reported tinnitus. These findings suggest neurobiological mechanisms behind auditory injuries in our military warfighters and are particularly relevant given tinnitus is not only a primary disability among veterans, but has also been demonstrated in active duty medical records for populations exposed to blast in training. Additionally, we found that differentially methylated regions associated with the genes CCDC68 and COMT track with sleep difficulties, and those within FMOD and TNXB track with pain and headache. Conclusion: Sleep disturbances, as well as tinnitus and chronic pain, are widely reported in U.S. military service members and veterans. As we have previously demonstrated, DNA methylation encapsulates lifetime exposure to blast. The current Wang et al. Methylation Pattern of Cumulative Blast data support previous findings and recapitulate transcriptional regulatory alterations in genes involved in sleep, auditory function, and pain. These data uncovered novel epigenetic and transcriptional regulatory mechanism underlying the etiological basis of these symptoms.

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Section: Tinnitusmentioning

confidence: 99%

DNA Methylation Patterns of Chronic Explosive Breaching in U.S. Military Warfighters

Wang

Wilson

et al. 2020

Front. Neurol.

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“…21 Studies of congenital microtia in humans have found that the focal adhesion pathway may affect the development of ear cartilage. 22 Our results revealed gene and lncRNA expression changes involved in mouse external ear embryonic development in mice with a point mutation in the Prkra gene. In particular, changes in the lncRNA expression profile were detected during mouse embryonic auricle development from E15.5 to E17.5, suggesting that the regulation of multiple lncRNAs may contribute to the process of external ear development.…”

Section: Discussionmentioning

confidence: 63%

Prkra Mutation Alters Long Noncoding RNA Expression During Embryonic External Ear Development

Liu

Jin

Lin

et al. 2022

Journal of Craniofacial Surgery

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Point mutations in the Prkra gene result in abnormalities in mouse external ear development; however, the regulatory mechanisms underlying this phenotype are unclear. This study evaluated long noncoding RNA (lncRNA) expression profiles in the outer ear tissues of embryos at E15.5 and E17.5 from the Prkra little ear mouse model using transcriptome sequencing. Differentially expressed lncRNAs between the experimental and control groups were identified and evaluated by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses. The results revealed various lncRNAs that contribute to the external ear development in Prkra mutant mice, some of which were involved in multiple developmental signaling pathways. There were expression changes in some key regulatory lncRNAs after point mutations in the Prkra gene, some of which were involved in multiple developmental signaling pathways, such as the Hippo, MAPK, and ErbB signaling pathways. These results provide insight into the regulatory mechanism underlying external ear embryonic development and reveal candidate lncRNAs.

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“…Studies have found that the focal adhesion pathway may be closely related to the formation of microtia, which may be because the outer ear cartilage is mainly composed of elastic cartilage, which can affect the development of cartilage, resulting in external ear malformation. 20 The main limitation of this study is that functional validation was not performed following the confirmation of differential cir-cRNA expression in the development of mouse external ear embryos.…”

Section: Discussionmentioning

confidence: 99%

Prkra Mutation Alters circRNA Expression During Embryonic External Ear Development

Liu

Jin

Lin

et al. 2022

Journal of Craniofacial Surgery

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: The changes in circRNA expression profile in the mouse external ear tissue during embryonic development to E15.5 and E17.5 can provide clues for the study of the regulation of external ear embryonic development. To understand the changes in gene regulation and expression of circRNA involved in mouse external ear embryonic development, a Prkra Little ear mouse model was used, and the changes in circRNA expression profiles were detected using next-generation sequencing. The changes in the expression of circRNA in the experimental group compared with those in the control group were identified using the find_circ and CiRi2 software, and the differentially expressed circRNAs were annotated via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. The results show that the development of mouse external ear embryos is regulated by circRNA expression.

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Target sequencing of 307 deafness genes identifies candidate genes implicated in microtia

Cited by 11 publications

References 26 publications

DNA Methylation Patterns of Chronic Explosive Breaching in U.S. Military Warfighters

DNA Methylation Patterns of Chronic Explosive Breaching in U.S. Military Warfighters

Prkra Mutation Alters Long Noncoding RNA Expression During Embryonic External Ear Development

Prkra Mutation Alters circRNA Expression During Embryonic External Ear Development

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