{"title":"一种新的纯合子TBC1D2B变异破坏了功能域,并提示神经发育障碍中Rab-GTPase的调节受损","authors":"Murat Ozturk, Cahide Bulut Arslan, Ekrem Akbulut, Esra Habiloglu, Esra Yaylı, Zehra Oya Uyguner","doi":"10.1002/dneu.22998","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p>Recent reports have linked biallelic loss-of-function variants in the <i>TBC1D2B</i> gene to neurodevelopmental disorder with seizures and gingival overgrowth (NEDSGO) (OMIM 619323), a rare condition characterized by seizures and gingival hyperplasia. However, due to the limited number of reported cases, the phenotypic diversity of this syndrome remains poorly characterized. This study reports four affected children from a consanguineous family in Türkiye, in whom a novel variant in this gene was identified. All individuals underwent clinical examination, electroencephalography (EEG), brain magnetic resonance imaging (MRI), histopathological evaluation, and genetic analyses. A novel homozygous truncating variant in the <i>TBC1D2B</i> gene was identified. In silico protein structure modeling was performed to investigate the potential impact of the variant. The identified c.323_324delinsAA; p.(Phe108Ter) variant causes premature protein truncation, resulting in the loss of key functional domains, such as Rab-GAP-TBC, coiled-coil, and PH (pleckstrin homology). All patients exhibited developmental delay (DD), epileptic seizures, gingival fibromatosis, and craniofacial anomalies. The growth delay seen in both of our patients, also described in an earlier case with the same gene variant, suggests that this may be a clinical feature of the syndrome. Binding pocket analysis revealed marked reductions in putative protein interaction regions, suggesting a loss-of-function effect due to the mutation. These findings reveal previously unrecognized aspects of both the genetic and clinical spectrum of NEDSGO syndrome caused by variants in the <i>TBC1D2B</i> gene. The resulting data underscore that disruption of structural protein regions directly contributes to the phenotype of this rare disorder.</p>\n </div>","PeriodicalId":11300,"journal":{"name":"Developmental Neurobiology","volume":"85 4","pages":""},"PeriodicalIF":2.3000,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A Novel Homozygous TBC1D2B Variant Disrupts Functional Domains and Suggests Impaired Rab-GTPase Regulation in Neurodevelopmental Disorder\",\"authors\":\"Murat Ozturk, Cahide Bulut Arslan, Ekrem Akbulut, Esra Habiloglu, Esra Yaylı, Zehra Oya Uyguner\",\"doi\":\"10.1002/dneu.22998\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <p>Recent reports have linked biallelic loss-of-function variants in the <i>TBC1D2B</i> gene to neurodevelopmental disorder with seizures and gingival overgrowth (NEDSGO) (OMIM 619323), a rare condition characterized by seizures and gingival hyperplasia. However, due to the limited number of reported cases, the phenotypic diversity of this syndrome remains poorly characterized. This study reports four affected children from a consanguineous family in Türkiye, in whom a novel variant in this gene was identified. All individuals underwent clinical examination, electroencephalography (EEG), brain magnetic resonance imaging (MRI), histopathological evaluation, and genetic analyses. A novel homozygous truncating variant in the <i>TBC1D2B</i> gene was identified. In silico protein structure modeling was performed to investigate the potential impact of the variant. The identified c.323_324delinsAA; p.(Phe108Ter) variant causes premature protein truncation, resulting in the loss of key functional domains, such as Rab-GAP-TBC, coiled-coil, and PH (pleckstrin homology). All patients exhibited developmental delay (DD), epileptic seizures, gingival fibromatosis, and craniofacial anomalies. The growth delay seen in both of our patients, also described in an earlier case with the same gene variant, suggests that this may be a clinical feature of the syndrome. Binding pocket analysis revealed marked reductions in putative protein interaction regions, suggesting a loss-of-function effect due to the mutation. These findings reveal previously unrecognized aspects of both the genetic and clinical spectrum of NEDSGO syndrome caused by variants in the <i>TBC1D2B</i> gene. The resulting data underscore that disruption of structural protein regions directly contributes to the phenotype of this rare disorder.</p>\\n </div>\",\"PeriodicalId\":11300,\"journal\":{\"name\":\"Developmental Neurobiology\",\"volume\":\"85 4\",\"pages\":\"\"},\"PeriodicalIF\":2.3000,\"publicationDate\":\"2025-09-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Developmental Neurobiology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/dneu.22998\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"DEVELOPMENTAL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Developmental Neurobiology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/dneu.22998","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"DEVELOPMENTAL BIOLOGY","Score":null,"Total":0}
A Novel Homozygous TBC1D2B Variant Disrupts Functional Domains and Suggests Impaired Rab-GTPase Regulation in Neurodevelopmental Disorder
Recent reports have linked biallelic loss-of-function variants in the TBC1D2B gene to neurodevelopmental disorder with seizures and gingival overgrowth (NEDSGO) (OMIM 619323), a rare condition characterized by seizures and gingival hyperplasia. However, due to the limited number of reported cases, the phenotypic diversity of this syndrome remains poorly characterized. This study reports four affected children from a consanguineous family in Türkiye, in whom a novel variant in this gene was identified. All individuals underwent clinical examination, electroencephalography (EEG), brain magnetic resonance imaging (MRI), histopathological evaluation, and genetic analyses. A novel homozygous truncating variant in the TBC1D2B gene was identified. In silico protein structure modeling was performed to investigate the potential impact of the variant. The identified c.323_324delinsAA; p.(Phe108Ter) variant causes premature protein truncation, resulting in the loss of key functional domains, such as Rab-GAP-TBC, coiled-coil, and PH (pleckstrin homology). All patients exhibited developmental delay (DD), epileptic seizures, gingival fibromatosis, and craniofacial anomalies. The growth delay seen in both of our patients, also described in an earlier case with the same gene variant, suggests that this may be a clinical feature of the syndrome. Binding pocket analysis revealed marked reductions in putative protein interaction regions, suggesting a loss-of-function effect due to the mutation. These findings reveal previously unrecognized aspects of both the genetic and clinical spectrum of NEDSGO syndrome caused by variants in the TBC1D2B gene. The resulting data underscore that disruption of structural protein regions directly contributes to the phenotype of this rare disorder.
期刊介绍:
Developmental Neurobiology (previously the Journal of Neurobiology ) publishes original research articles on development, regeneration, repair and plasticity of the nervous system and on the ontogeny of behavior. High quality contributions in these areas are solicited, with an emphasis on experimental as opposed to purely descriptive work. The Journal also will consider manuscripts reporting novel approaches and techniques for the study of the development of the nervous system as well as occasional special issues on topics of significant current interest. We welcome suggestions on possible topics from our readers.