IQSEC2 p.Asp894Asn variant significantly destabilizes protein structure, linked to X-linked Intellectual Disability

X-linked Intellectual Disability (XLID) represents a diverse group of neurodevelopmental disorders stemming from genetic defects on the X chromosome. Patients typically exhibit cognitive dysfunction and difficulties adapting to social environments, often defined by an IQ below 70. Current therapeutic interventions for XLID are largely symptomatic, highlighting a critical need for improved understanding of underlying genetic causes and their functional consequences. The IQSEC2 gene, located on the X chromosome, is implicated in neuronal function and development, making its variants key candidates for investigating the molecular basis of XLID.

Researchers investigated a consanguineous Pashtun family affected by XLID. Whole exome sequencing was performed on the proband, identifying a hemizygous variant, c.2680G>A (p.Asp894Asn), in the IQSEC2 gene. This finding was subsequently validated using Sanger sequencing. To understand the functional impact of this mutation, structural bioinformatics approaches were employed to deduce and compare the three-dimensional structures of both the wild-type and the mutated IQSEC2 (Asp894Asn) protein. Molecular dynamics simulations were then conducted to analyze structural changes and stability differences between the two protein forms.

Molecular dynamics simulations revealed that the D894N mutation in IQSEC2 significantly destabilizes the protein structure. This destabilization was evidenced by several key metrics: an increase in backbone RMSD (Root Mean Square Deviation), indicating greater overall structural deviation from the initial conformation, and elevated residue-level fluctuations (RMSF), signifying increased flexibility and disorder at specific amino acid positions. The simulations also demonstrated altered intramolecular interactions within the mutant protein. These collective changes led to enhanced conformational variability in the mutant IQSEC2 protein compared to its wild-type counterpart. The study's findings provide a clear molecular explanation for the pathogenicity of the p.Asp894Asn variant. > The D894N mutation in IQSEC2 significantly destabilizes the protein structure, leading to increased backbone RMSD and elevated residue-level fluctuations (RMSF), confirming its pathogenic role.