Characterization of pathogenic missense mutations in nuclear encoded mitochondrial dynamin -1 like protein

The DNM1L gene encodes the dynamin-related protein, Drp1, essential for mitochondrial fission. Impaired mitochondrial division contributes to cardiovascular, neurodegenerative, and metabolic disorders. This study aimed to identify and analyse deleterious nonsynonymous single nucleotide polymorphisms (nsSNPs) in DNM1L that may impair protein function.

An integrated in silico strategy combining multiple predictive tools (SIFT, PolyPhen-2, PhD-SNP, PANTHER, Meta-SNP, FATHMM, I-Mutant 2.0, INPS-MD, Medusa, MutPred2, DynaMut2, ConSurf, NetSurfP-2.0, STRING, GeneMANIA) was used to identify deleterious nonsynonymous SNPs (nsSNPs) in DNM1L and evaluate their structural and functional effects.

Eleven nsSNPs (A395D, V417G, R60W, etc.) were consistently predicted to be pathogenic. These variants occurred at conserved residues and induced significant changes in protein stability, flexibility, and interaction potential. Functional annotations suggested possible alterations in metal binding, secondary structure, and post-translational modifications.

The identified DNM1L variants may compromise Drp1 function and contribute to mitochondrial dysfunction underlying disease mechanisms. This study provides a computational basis for future experimental validation and clinical exploration of DNM1L-associated disorders. These variants may underlie mitochondrial dysfunction contributing to neurodegenerative and metabolic disorders.