Intisar Koch, Maya Slovik, Yuling Zhang, Bingyu Liu, Martin Rennie, Emily Konz, Benjamin Cogne, Muhannad Daana, Laura Davids, Illja J Diets, Nina B Gold, Alexander M Holtz, Bertrand Isidor, Hagar Mor-Shaked, Juanita Neira Fresneda, Karen Y Niederhoffer, Mathilde Nizon, Rolph Pfundt, Meh Simon, Apa Stegmann, Maria J Guillen Sacoto, Marijke Wevers, Tahsin Stefan Barakat, Shira Yanovsky-Dagan, Boyko S Atanassov, Rachel Toth, Chengjiang Gao, Francisco Bustos, Tamar Harel
{"title":"X 连锁智力障碍的基础 USP27X 变异通过不同的机制破坏蛋白质功能。","authors":"Intisar Koch, Maya Slovik, Yuling Zhang, Bingyu Liu, Martin Rennie, Emily Konz, Benjamin Cogne, Muhannad Daana, Laura Davids, Illja J Diets, Nina B Gold, Alexander M Holtz, Bertrand Isidor, Hagar Mor-Shaked, Juanita Neira Fresneda, Karen Y Niederhoffer, Mathilde Nizon, Rolph Pfundt, Meh Simon, Apa Stegmann, Maria J Guillen Sacoto, Marijke Wevers, Tahsin Stefan Barakat, Shira Yanovsky-Dagan, Boyko S Atanassov, Rachel Toth, Chengjiang Gao, Francisco Bustos, Tamar Harel","doi":"10.26508/lsa.202302258","DOIUrl":null,"url":null,"abstract":"<p><p>Neurodevelopmental disorders with intellectual disability (ND/ID) are a heterogeneous group of diseases driving lifelong deficits in cognition and behavior with no definitive cure. X-linked intellectual disability disorder 105 (XLID105, #300984; OMIM) is a ND/ID driven by hemizygous variants in the <i>USP27X</i> gene encoding a protein deubiquitylase with a role in cell proliferation and neural development. Currently, only four genetically diagnosed individuals from two unrelated families have been described with limited clinical data. Furthermore, the mechanisms underlying the disorder are unknown. Here, we report 10 new XLID105 individuals from nine families and determine the impact of gene variants on USP27X protein function. Using a combination of clinical genetics, bioinformatics, biochemical, and cell biology approaches, we determined that XLID105 variants alter USP27X protein biology via distinct mechanisms including changes in developmentally relevant protein-protein interactions and deubiquitylating activity. Our data better define the phenotypic spectrum of XLID105 and suggest that XLID105 is driven by USP27X functional disruption. Understanding the pathogenic mechanisms of XLID105 variants will provide molecular insight into USP27X biology and may create the potential for therapy development.</p>","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 3","pages":""},"PeriodicalIF":3.3000,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10770416/pdf/","citationCount":"0","resultStr":"{\"title\":\"<i>USP27X</i> variants underlying X-linked intellectual disability disrupt protein function via distinct mechanisms.\",\"authors\":\"Intisar Koch, Maya Slovik, Yuling Zhang, Bingyu Liu, Martin Rennie, Emily Konz, Benjamin Cogne, Muhannad Daana, Laura Davids, Illja J Diets, Nina B Gold, Alexander M Holtz, Bertrand Isidor, Hagar Mor-Shaked, Juanita Neira Fresneda, Karen Y Niederhoffer, Mathilde Nizon, Rolph Pfundt, Meh Simon, Apa Stegmann, Maria J Guillen Sacoto, Marijke Wevers, Tahsin Stefan Barakat, Shira Yanovsky-Dagan, Boyko S Atanassov, Rachel Toth, Chengjiang Gao, Francisco Bustos, Tamar Harel\",\"doi\":\"10.26508/lsa.202302258\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Neurodevelopmental disorders with intellectual disability (ND/ID) are a heterogeneous group of diseases driving lifelong deficits in cognition and behavior with no definitive cure. X-linked intellectual disability disorder 105 (XLID105, #300984; OMIM) is a ND/ID driven by hemizygous variants in the <i>USP27X</i> gene encoding a protein deubiquitylase with a role in cell proliferation and neural development. Currently, only four genetically diagnosed individuals from two unrelated families have been described with limited clinical data. Furthermore, the mechanisms underlying the disorder are unknown. Here, we report 10 new XLID105 individuals from nine families and determine the impact of gene variants on USP27X protein function. Using a combination of clinical genetics, bioinformatics, biochemical, and cell biology approaches, we determined that XLID105 variants alter USP27X protein biology via distinct mechanisms including changes in developmentally relevant protein-protein interactions and deubiquitylating activity. Our data better define the phenotypic spectrum of XLID105 and suggest that XLID105 is driven by USP27X functional disruption. Understanding the pathogenic mechanisms of XLID105 variants will provide molecular insight into USP27X biology and may create the potential for therapy development.</p>\",\"PeriodicalId\":18081,\"journal\":{\"name\":\"Life Science Alliance\",\"volume\":\"7 3\",\"pages\":\"\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2024-01-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10770416/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Life Science Alliance\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.26508/lsa.202302258\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/3/1 0:00:00\",\"PubModel\":\"Print\",\"JCR\":\"Q1\",\"JCRName\":\"BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Life Science Alliance","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.26508/lsa.202302258","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/3/1 0:00:00","PubModel":"Print","JCR":"Q1","JCRName":"BIOLOGY","Score":null,"Total":0}
USP27X variants underlying X-linked intellectual disability disrupt protein function via distinct mechanisms.
Neurodevelopmental disorders with intellectual disability (ND/ID) are a heterogeneous group of diseases driving lifelong deficits in cognition and behavior with no definitive cure. X-linked intellectual disability disorder 105 (XLID105, #300984; OMIM) is a ND/ID driven by hemizygous variants in the USP27X gene encoding a protein deubiquitylase with a role in cell proliferation and neural development. Currently, only four genetically diagnosed individuals from two unrelated families have been described with limited clinical data. Furthermore, the mechanisms underlying the disorder are unknown. Here, we report 10 new XLID105 individuals from nine families and determine the impact of gene variants on USP27X protein function. Using a combination of clinical genetics, bioinformatics, biochemical, and cell biology approaches, we determined that XLID105 variants alter USP27X protein biology via distinct mechanisms including changes in developmentally relevant protein-protein interactions and deubiquitylating activity. Our data better define the phenotypic spectrum of XLID105 and suggest that XLID105 is driven by USP27X functional disruption. Understanding the pathogenic mechanisms of XLID105 variants will provide molecular insight into USP27X biology and may create the potential for therapy development.
期刊介绍:
Life Science Alliance is a global, open-access, editorially independent, and peer-reviewed journal launched by an alliance of EMBO Press, Rockefeller University Press, and Cold Spring Harbor Laboratory Press. Life Science Alliance is committed to rapid, fair, and transparent publication of valuable research from across all areas in the life sciences.