همایش ملی بیوانفورماتیک ایران

صفحه اصلی / 4th international edition and 13th Iranian Conference on Bioinformatics

Discovery and Bioinformatics Analysis of a Novel Variant in the HERC2 Gene Associated with Intellectual Developmental Disorder

نویسندگان :

Asal Asghari Sarfaraz¹ Neda Jabbarpour² Mortaza Bonyadi³ Mohammad Khalaj-Kondory⁴

1- Animal Biology Department, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran. 2- Animal Biology Department, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran. 3- Center of Excellence for Biodiversity, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran. 4- Animal Biology Department, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.

کلمات کلیدی :

HERC2 gene،HECT domain،novel variant،Whole-Exome-Sequencing (WES)

چکیده :

Intellectual Developmental Disorder is a neurodevelopmental disorder defined by considerable deficits in intellectual functioning and adaptive abilities (Deliu et al., 2018; Patel et al., 2020). The frequency of Intellectual Developmental Disorder varies by population, with estimates between 1% and 3% (Gürkan et al., 2020; Maia et al., 2021; McKenzie et al., 2016). A 10-year-old boy, born into a consanguineous family of the Iranian-Azeri Turkish ethnic group, has been diagnosed with autosomal recessive Intellectual Developmental Disorder. His sister has also received the same diagnosis. He has been referred to a genetic laboratory for Whole Exome Sequencing analysis. To assess the prevalence of the identified variant associated with Intellectual Developmental Disorder in the Iranian-Azeri Turkish population, a study was conducted using Whole Exome Sequencing data from a cohort of 400 individuals. The proband's DNA was extracted, quantified, and then analyzed using Whole Exome Sequencing (Li and Durbin, 2010, 2009). The impact of the identified variants on the structure and function of the encoded proteins was assessed using various web-based tools (Pettersen et al., 2004). To validate the identified pathogenic variants in the probands, Sanger sequencing was carried out on both the affected patients and, if possible, other family members. Whole Exome Sequencing analysis detected a homozygous transition from C to T at position 14215 within exon ninety-two of the HERC2 gene. This result was confirmed by Sanger sequencing, which showed a genetic alteration that produces an early stop codon at amino acid position 4739. The parents were identified as heterozygous for the mutation, while the affected sister, who unfortunately passed away a few months later, was also homozygous for the variant. Utilizing the I-TASSER (Zheng et al., 2021) web-based tool, it was revealed that the mutant mRNA containing the premature nonsense mutation encodes a protein that exhibits significant differences in both function and length when compared to the wild-type protein. The truncation of the Hect domain is likely to disrupt its function. The mutation's lack of presence in both our cohort and public datasets, along with its confirmed pathogenicity, implies that the HERC2 protein will likely lose its function. In this study, we report a novel homozygous variant that leads to a premature stop codon in exon ninety-two of the HERC2 gene. The premature nonsense mutation (p.Arg4739Ter) is found in the HECT domain, leading to a mutant mRNA that encodes a protein with substantial disruption of the HECT domain, which affects its structure and functionality. The carboxy-terminal region of the HERC2 protein is essential for the catalytic activity of ubiquitination. The cysteine residue (Cys4762) is vital for forming a transient thioester bond with ubiquitin. This bond allows ubiquitin to be transferred to either a lysine residue or the amino terminus of the target protein (García-Cano et al., 2019; Mathieu et al., 2021; Sala-Gaston et al., 2020). This reinforces the notion that the mutation disrupts the protein's normal function and confirms its pathogenicity.