Identification and bioinformatics analysis of a novel variant in the HERC2 gene in a patient with intellectual developmental disorder.

IF 1.8 4区 医学 Q3 GENETICS & HEREDITY Journal of neurogenetics Pub Date : 2024-03-01 Epub Date: 2024-06-17 DOI:10.1080/01677063.2024.2365634
Asal Asghari Sarfaraz, Neda Jabbarpour, Mortaza Bonyadi, Mohammad Khalaj-Kondory
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Abstract

HERC2-associated neurodevelopmental-disorders(NDD) encompass a cluster of medical conditions that arise from genetic mutations occurring within the HERC2 gene. These disorders can manifest a spectrum of symptoms that impact the brain and nervous system, including delayed psychomotor development, severe mental retardation, seizures and autistic features. Whole-Exome-Sequencing(WES) was performed on a ten-year-old male patient referred to the genetic center for genetic analysis. Blood samples were collected from the proband, his parents, and his sister to extract DNA. PCR-Sanger-sequencing was utilized to validate the findings obtained from WES. In order to obtain a more thorough understanding of the impact of the mutation, an extensive analysis was conducted using bioinformatics tools. WES data analysis identified a homozygous single nucleotide change(C > T) at position c14215 located in exon ninety-two of the HERC2 gene (NC_000015.10(NM_004667.6):c.14215C > T). The absence of this mutation among our cohort composed of four hundred normal healthy adults from the same ethnic group, and its absence in any other population database, confirms the pathogenicity of the mutation. This study revealed that the substitution of arginine with a stop codon within the Hect domain caused a premature stop codon at position 4739(p.Arg4739Ter). This mutation significantly results in the production of a truncated HERC2 protein with an incomplete HECT domain. In the final stage of ubiquitin attachment, HECT E3 ubiquitin ligases play a catalytic role by creating a thiolester intermediate using their conserved catalytic cysteine (Cys4762). This intermediate is formed before ubiquitin is transferred to a substrate protein. The truncation of the HERC2 protein is expected to disrupt its ability to perform this function, which could potentially hinder important regulatory processes related to the development and maintenance of synapses. The identification of a novel pathogenic variant, NC_000015.10(NM_004667.6):c.14215C > T, located within the ninety-two exon of the HERC2 gene, is notable for its association with an autosomal recessive inheritance pattern in cases of Intellectual Developmental Disorder(IDD). In the end, this variant could potentially play a part in the underlying mechanisms leading to the onset of intellectual developmental disorder.

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一名智力发育障碍患者的 HERC2 基因新型变异的鉴定和生物信息学分析。
HERC2 相关神经发育障碍(NDD)是由 HERC2 基因突变引起的一组疾病。这些疾病可表现出一系列影响大脑和神经系统的症状,包括精神运动发育迟缓、严重智力迟钝、癫痫发作和自闭症特征。为进行基因分析,遗传中心对一名十岁的男性患者进行了全基因组测序(WES)。研究人员采集了患者、其父母和姐姐的血液样本,提取 DNA。利用 PCR-Sanger 测序验证了 WES 的结果。为了更透彻地了解突变的影响,利用生物信息学工具进行了广泛的分析。WES 数据分析确定了位于 HERC2 基因第 92 号外显子 c14215 位的同源单核苷酸变化(C > T)(NC_000015.10(NM_004667.6):c.14215C > T)。在我们由四百名来自同一族群的正常健康成年人组成的队列中,没有发现这一突变,而在其他人群数据库中也没有发现,这证实了该突变的致病性。这项研究发现,在 Hect 结构域中,精氨酸与终止密码子的替换导致在 4739 位出现过早的终止密码子(p.Arg4739Ter)。这一突变极大地导致产生了具有不完整 HECT 结构域的截短 HERC2 蛋白。在泛素连接的最后阶段,HECT E3 泛素连接酶利用其保守的催化半胱氨酸(Cys4762)产生硫醇酯中间体,从而发挥催化作用。这种中间体是在泛素转移到底物蛋白质之前形成的。HERC2 蛋白的截短预计会破坏其执行这一功能的能力,从而有可能阻碍与突触的发育和维持有关的重要调节过程。在 HERC2 基因的九十二个外显子中发现了一个新的致病变体 NC_000015.10(NM_004667.6):c.14215C>T,该变体与智力发育障碍(IDD)病例的常染色体隐性遗传模式有关。最终,该变异有可能在导致智力发育障碍发病的潜在机制中扮演重要角色。
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来源期刊
Journal of neurogenetics
Journal of neurogenetics 医学-神经科学
CiteScore
4.40
自引率
0.00%
发文量
13
审稿时长
>12 weeks
期刊介绍: The Journal is appropriate for papers on behavioral, biochemical, or cellular aspects of neural function, plasticity, aging or disease. In addition to analyses in the traditional genetic-model organisms, C. elegans, Drosophila, mouse and the zebrafish, the Journal encourages submission of neurogenetic investigations performed in organisms not easily amenable to experimental genetics. Such investigations might, for instance, describe behavioral differences deriving from genetic variation within a species, or report human disease studies that provide exceptional insights into biological mechanisms
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