Morag A Lewis, Maria Lachgar-Ruiz, Francesca Di Domenico, Graham Duddy, Jing Chen, Sergio Fernandez, Matias Morin, Gareth Williams, Miguel Angel Moreno Pelayo, Karen P Steel
{"title":"携带人类 MIR96 基因突变的小鼠听力损失的病理机制和候选治疗方法。","authors":"Morag A Lewis, Maria Lachgar-Ruiz, Francesca Di Domenico, Graham Duddy, Jing Chen, Sergio Fernandez, Matias Morin, Gareth Williams, Miguel Angel Moreno Pelayo, Karen P Steel","doi":"10.1186/s13073-024-01394-5","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Progressive hearing loss is a common problem in the human population with no effective therapeutics currently available. However, it has a strong genetic contribution, and investigating the genes and regulatory interactions underlying hearing loss offers the possibility of identifying therapeutic candidates. Mutations in regulatory genes are particularly useful for this, and an example is the microRNA miR-96, a post-transcriptional regulator which controls hair cell maturation. Mice and humans carrying mutations in miR-96 all exhibit hearing impairment, in homozygosis if not in heterozygosis, but different mutations result in different physiological, structural and transcriptional phenotypes.</p><p><strong>Methods: </strong>Here we present our characterisation of two lines of mice carrying different human mutations knocked-in to Mir96. We have carried out auditory brainstem response tests to examine their hearing with age and after noise exposure and have used confocal and scanning electron microscopy to examine the ultrastructure of the organ of Corti and hair cell synapses. Bulk RNA-seq was carried out on the organs of Corti of postnatal mice, followed by bioinformatic analyses to identify candidate targets.</p><p><strong>Results: </strong>While mice homozygous for either mutation are profoundly deaf from 2 weeks old, the heterozygous phenotypes differ markedly, with only one mutation resulting in hearing impairment in heterozygosis. Investigations of the structural phenotype showed that one mutation appears to lead to synaptic defects, while the other has a much more severe effect on the hair cell stereociliary bundles. Transcriptome analyses revealed a wide range of misregulated genes in both mutants which were notably dissimilar. We used the transcriptome analyses to investigate candidate therapeutics, and tested one, finding that it delayed the progression of hearing loss in heterozygous mice.</p><p><strong>Conclusions: </strong>Our work adds further support for the importance of the gain of novel targets in microRNA mutants and offers a proof of concept for the identification of pharmacological interventions to maintain hearing.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"121"},"PeriodicalIF":10.4000,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11492784/pdf/","citationCount":"0","resultStr":"{\"title\":\"Pathological mechanisms and candidate therapeutic approaches in the hearing loss of mice carrying human MIR96 mutations.\",\"authors\":\"Morag A Lewis, Maria Lachgar-Ruiz, Francesca Di Domenico, Graham Duddy, Jing Chen, Sergio Fernandez, Matias Morin, Gareth Williams, Miguel Angel Moreno Pelayo, Karen P Steel\",\"doi\":\"10.1186/s13073-024-01394-5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Progressive hearing loss is a common problem in the human population with no effective therapeutics currently available. However, it has a strong genetic contribution, and investigating the genes and regulatory interactions underlying hearing loss offers the possibility of identifying therapeutic candidates. Mutations in regulatory genes are particularly useful for this, and an example is the microRNA miR-96, a post-transcriptional regulator which controls hair cell maturation. Mice and humans carrying mutations in miR-96 all exhibit hearing impairment, in homozygosis if not in heterozygosis, but different mutations result in different physiological, structural and transcriptional phenotypes.</p><p><strong>Methods: </strong>Here we present our characterisation of two lines of mice carrying different human mutations knocked-in to Mir96. We have carried out auditory brainstem response tests to examine their hearing with age and after noise exposure and have used confocal and scanning electron microscopy to examine the ultrastructure of the organ of Corti and hair cell synapses. Bulk RNA-seq was carried out on the organs of Corti of postnatal mice, followed by bioinformatic analyses to identify candidate targets.</p><p><strong>Results: </strong>While mice homozygous for either mutation are profoundly deaf from 2 weeks old, the heterozygous phenotypes differ markedly, with only one mutation resulting in hearing impairment in heterozygosis. Investigations of the structural phenotype showed that one mutation appears to lead to synaptic defects, while the other has a much more severe effect on the hair cell stereociliary bundles. Transcriptome analyses revealed a wide range of misregulated genes in both mutants which were notably dissimilar. We used the transcriptome analyses to investigate candidate therapeutics, and tested one, finding that it delayed the progression of hearing loss in heterozygous mice.</p><p><strong>Conclusions: </strong>Our work adds further support for the importance of the gain of novel targets in microRNA mutants and offers a proof of concept for the identification of pharmacological interventions to maintain hearing.</p>\",\"PeriodicalId\":12645,\"journal\":{\"name\":\"Genome Medicine\",\"volume\":\"16 1\",\"pages\":\"121\"},\"PeriodicalIF\":10.4000,\"publicationDate\":\"2024-10-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11492784/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Genome Medicine\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1186/s13073-024-01394-5\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Genome Medicine","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1186/s13073-024-01394-5","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
Pathological mechanisms and candidate therapeutic approaches in the hearing loss of mice carrying human MIR96 mutations.
Background: Progressive hearing loss is a common problem in the human population with no effective therapeutics currently available. However, it has a strong genetic contribution, and investigating the genes and regulatory interactions underlying hearing loss offers the possibility of identifying therapeutic candidates. Mutations in regulatory genes are particularly useful for this, and an example is the microRNA miR-96, a post-transcriptional regulator which controls hair cell maturation. Mice and humans carrying mutations in miR-96 all exhibit hearing impairment, in homozygosis if not in heterozygosis, but different mutations result in different physiological, structural and transcriptional phenotypes.
Methods: Here we present our characterisation of two lines of mice carrying different human mutations knocked-in to Mir96. We have carried out auditory brainstem response tests to examine their hearing with age and after noise exposure and have used confocal and scanning electron microscopy to examine the ultrastructure of the organ of Corti and hair cell synapses. Bulk RNA-seq was carried out on the organs of Corti of postnatal mice, followed by bioinformatic analyses to identify candidate targets.
Results: While mice homozygous for either mutation are profoundly deaf from 2 weeks old, the heterozygous phenotypes differ markedly, with only one mutation resulting in hearing impairment in heterozygosis. Investigations of the structural phenotype showed that one mutation appears to lead to synaptic defects, while the other has a much more severe effect on the hair cell stereociliary bundles. Transcriptome analyses revealed a wide range of misregulated genes in both mutants which were notably dissimilar. We used the transcriptome analyses to investigate candidate therapeutics, and tested one, finding that it delayed the progression of hearing loss in heterozygous mice.
Conclusions: Our work adds further support for the importance of the gain of novel targets in microRNA mutants and offers a proof of concept for the identification of pharmacological interventions to maintain hearing.
期刊介绍:
Genome Medicine is an open access journal that publishes outstanding research applying genetics, genomics, and multi-omics to understand, diagnose, and treat disease. Bridging basic science and clinical research, it covers areas such as cancer genomics, immuno-oncology, immunogenomics, infectious disease, microbiome, neurogenomics, systems medicine, clinical genomics, gene therapies, precision medicine, and clinical trials. The journal publishes original research, methods, software, and reviews to serve authors and promote broad interest and importance in the field.