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ORIGINAL RESEARCH

Preliminary Study on Clinical Characteristics and Pathogenesis of IQSEC2 Mutations Patients

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Pages 289-318 | Received 25 Jan 2024, Accepted 18 May 2024, Published online: 30 May 2024
 

Abstract

Background

The IQ motif and Sec7 domain ArfGEF 2 (IQSEC2), an X-linked gene that encodes the BRAG1 protein, is a guanine nucleotide exchange factor for the ADP ribosylation factor (ARF) protein family in the small guanosine triphosphate (GTP) binding protein. Mutations in this gene result in disorders such as intellectual disability (ID) and epilepsy. In this study, we analyze the clinical features of two patients with IQSEC2-mutation-related disease and discuss their possible pathogenesis.

Methods

The two patients were diagnosed with ID and epilepsy. Genetic testing was performed using whole-exome sequencing, and the three-dimensional protein structure was analyzed. UCSC Genome Browser was used to analyze the conservation of IQSEC2 in different species. We compared IQSEC2 expression in the proband families with that in a control group, as well as the expression of the postsynaptic identity protein 95 (PSD-95), synapse-associated protein 97 (SAP97), ADP ribosylation factor 6 (ARF-6), and insulin receptor substrate 53kDa (IRSP53) genes interacting with IQSEC2.

Results

We identified two semi-zygote mutations located in conserved positions in different species: an unreported de novo mutation, C.3576C>A (p. Tyr1192*), and a known mutation, c.2983C>T (p. Arg995Trp). IQSEC2 mutations resulted in significant changes in the predicted three-dimensional protein structure, while its expression in the two probands was significantly lower than that in the age-matched control group, and IQSEC2 expression in proband 1 was lower than that in his family members. The expression levels of PSD-95, ARF-6, and SAP97, IRSP 53, which interact with IQSEC2, were also significantly different from those in the family members and age-matched healthy children.

Conclusion

The clinical phenotype resulting from IQSEC2 mutations can be explained by the significant decrease in its expression, loss of function of the mutant protein, and change in the expression of related genes. Our results provide novel insights into the molecular phenotype conferred by the IQSEC2 variants.

Ethics Approval and Consent to Participate

The study was approved by the Ethics Committee of Shanghai Children’s Hospital (Approval number: 2019R071-F03) and complies with the ethical principles of the Helsinki Declaration. And the authors have obtained informed consent from the patient’s guardian regarding the publication of the article.The parents/guardians of both patients have agreed to publish case details and institutional approval was not required to publish case details.

Acknowledgments

We would like to express our gratitude to the patients and their parents for their cooperation. We would also like to thank Chao Wang for his help during this study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

This work was supported by grants from the Shanghai Key Clinical Specialty Project (grant number shslczdzk05705), Scientific Research Fund of China Association Against Epilepsy (grant number CJ-A-2021-07); National Fund Cultivation Special Project of Shanghai Children’s Hospital (grant number 2021YGZQ05) and Scientific Research Fund of China Association Against Epilepsy (CX-2022-013).