A Novel Homozygous TBC1D2B Variant Disrupts Functional Domains and Suggests Impaired Rab-GTPase Regulation in Neurodevelopmental Disorder

IF 2.3 4区 医学 Q2 DEVELOPMENTAL BIOLOGY
Murat Ozturk, Cahide Bulut Arslan, Ekrem Akbulut, Esra Habiloglu, Esra Yaylı, Zehra Oya Uyguner
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引用次数: 0

Abstract

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.

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
最近的报道将TBC1D2B基因的双等位基因功能丧失变异与癫痫发作和牙龈过度生长的神经发育障碍(NEDSGO) (OMIM 619323)联系起来,NEDSGO是一种罕见的疾病,以癫痫发作和牙龈增生为特征。然而,由于报告的病例数量有限,该综合征的表型多样性仍然缺乏特征。本研究报告了来自基耶省一个近亲家庭的四名患病儿童,在他们身上发现了该基因的一种新变体。所有患者均接受了临床检查、脑电图(EEG)、脑磁共振成像(MRI)、组织病理学评估和遗传分析。在TBC1D2B基因中发现了一个新的纯合子截断变异。在硅中进行蛋白质结构建模以研究该变异的潜在影响。已识别的c.323_324delinsAA;p.(Phe108Ter)变异导致蛋白质过早截断,导致关键功能域的缺失,如Rab-GAP-TBC、coil -coil和PH (pleckstrin homology)。所有患者均表现出发育迟缓(DD)、癫痫发作、牙龈纤维瘤病和颅面异常。在我们的两位患者身上看到的生长延迟,也在早期的一个具有相同基因变异的病例中描述过,表明这可能是该综合征的临床特征。结合口袋分析显示,假定的蛋白质相互作用区域明显减少,表明由于突变导致功能丧失。这些发现揭示了以前未被认识的由TBC1D2B基因变异引起的NEDSGO综合征的遗传和临床谱方面。结果数据强调,结构蛋白区域的破坏直接导致这种罕见疾病的表型。
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来源期刊
Developmental Neurobiology
Developmental Neurobiology 生物-发育生物学
CiteScore
6.50
自引率
0.00%
发文量
45
审稿时长
4-8 weeks
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.
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