Daniel C S Tan, Seonghee Jung, Yuanyuan Deng, Nicolle Morey, Gabriella Chan, Andre Bongers, Yazi D Ke, Lars M Ittner, Fabien Delerue
{"title":"PLP1靶向反义寡核苷酸可改善FOXG1综合征小鼠的病情","authors":"Daniel C S Tan, Seonghee Jung, Yuanyuan Deng, Nicolle Morey, Gabriella Chan, Andre Bongers, Yazi D Ke, Lars M Ittner, Fabien Delerue","doi":"10.3390/ijms251910846","DOIUrl":null,"url":null,"abstract":"<p><p>FOXG1 syndrome is a rare neurodevelopmental disorder of the telencephalon, for which there is no cure. Underlying heterozygous pathogenic variants in the <i>Forkhead Box G1</i> (<i>FOXG1</i>) gene with resulting impaired or loss of FOXG1 function lead to severe neurological impairments. Here, we report a patient with a de novo pathogenic single nucleotide deletion c.946del (p.Leu316Cysfs*10) of the <i>FOXG1</i> gene that causes a premature protein truncation. To study this variant in vivo, we generated and characterized <i>Foxg1</i> c946del mice that recapitulate hallmarks of the human disorder. Accordingly, heterozygous <i>Foxg1</i> c946del mice display neurological symptoms with aberrant neuronal networks and increased seizure susceptibility. Gene expression profiling identified increased oligodendrocyte- and myelination-related gene clusters. Specifically, we showed that expression of the c946del mutant and of other pathogenic <i>FOXG1</i> variants correlated with overexpression of <i>proteolipid protein 1</i> (<i>Plp1</i>), a gene linked to white matter disorders. Postnatal administration of <i>Plp1</i>-targeting antisense oligonucleotides (ASOs) in <i>Foxg1</i> c946del mice improved neurological deficits. Our data suggest Plp1 as a new target for therapeutic strategies mitigating disease phenotypes in FOXG1 syndrome patients.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":5.6000,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11477415/pdf/","citationCount":"0","resultStr":"{\"title\":\"PLP1-Targeting Antisense Oligonucleotides Improve FOXG1 Syndrome Mice.\",\"authors\":\"Daniel C S Tan, Seonghee Jung, Yuanyuan Deng, Nicolle Morey, Gabriella Chan, Andre Bongers, Yazi D Ke, Lars M Ittner, Fabien Delerue\",\"doi\":\"10.3390/ijms251910846\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>FOXG1 syndrome is a rare neurodevelopmental disorder of the telencephalon, for which there is no cure. Underlying heterozygous pathogenic variants in the <i>Forkhead Box G1</i> (<i>FOXG1</i>) gene with resulting impaired or loss of FOXG1 function lead to severe neurological impairments. Here, we report a patient with a de novo pathogenic single nucleotide deletion c.946del (p.Leu316Cysfs*10) of the <i>FOXG1</i> gene that causes a premature protein truncation. To study this variant in vivo, we generated and characterized <i>Foxg1</i> c946del mice that recapitulate hallmarks of the human disorder. Accordingly, heterozygous <i>Foxg1</i> c946del mice display neurological symptoms with aberrant neuronal networks and increased seizure susceptibility. Gene expression profiling identified increased oligodendrocyte- and myelination-related gene clusters. Specifically, we showed that expression of the c946del mutant and of other pathogenic <i>FOXG1</i> variants correlated with overexpression of <i>proteolipid protein 1</i> (<i>Plp1</i>), a gene linked to white matter disorders. Postnatal administration of <i>Plp1</i>-targeting antisense oligonucleotides (ASOs) in <i>Foxg1</i> c946del mice improved neurological deficits. Our data suggest Plp1 as a new target for therapeutic strategies mitigating disease phenotypes in FOXG1 syndrome patients.</p>\",\"PeriodicalId\":14156,\"journal\":{\"name\":\"International Journal of Molecular Sciences\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2024-10-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11477415/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International Journal of Molecular Sciences\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.3390/ijms251910846\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Molecular Sciences","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.3390/ijms251910846","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
FOXG1 syndrome is a rare neurodevelopmental disorder of the telencephalon, for which there is no cure. Underlying heterozygous pathogenic variants in the Forkhead Box G1 (FOXG1) gene with resulting impaired or loss of FOXG1 function lead to severe neurological impairments. Here, we report a patient with a de novo pathogenic single nucleotide deletion c.946del (p.Leu316Cysfs*10) of the FOXG1 gene that causes a premature protein truncation. To study this variant in vivo, we generated and characterized Foxg1 c946del mice that recapitulate hallmarks of the human disorder. Accordingly, heterozygous Foxg1 c946del mice display neurological symptoms with aberrant neuronal networks and increased seizure susceptibility. Gene expression profiling identified increased oligodendrocyte- and myelination-related gene clusters. Specifically, we showed that expression of the c946del mutant and of other pathogenic FOXG1 variants correlated with overexpression of proteolipid protein 1 (Plp1), a gene linked to white matter disorders. Postnatal administration of Plp1-targeting antisense oligonucleotides (ASOs) in Foxg1 c946del mice improved neurological deficits. Our data suggest Plp1 as a new target for therapeutic strategies mitigating disease phenotypes in FOXG1 syndrome patients.
期刊介绍:
The International Journal of Molecular Sciences (ISSN 1422-0067) provides an advanced forum for chemistry, molecular physics (chemical physics and physical chemistry) and molecular biology. It publishes research articles, reviews, communications and short notes. Our aim is to encourage scientists to publish their theoretical and experimental results in as much detail as possible. Therefore, there is no restriction on the length of the papers or the number of electronics supplementary files. For articles with computational results, the full experimental details must be provided so that the results can be reproduced. Electronic files regarding the full details of the calculation and experimental procedure, if unable to be published in a normal way, can be deposited as supplementary material (including animated pictures, videos, interactive Excel sheets, software executables and others).