New insights into HPDL protein: identification of a novel Bi-allelic variant, docking simulation study, and literature review

BACKGROUND: Hereditary Spastic Paraplegia (HSP) is a rare neurodegenerative disorder causing progressive weakness and spasticity in the lower limbs. variants in the HPDL gene are linked to Spastic Paraplegia 83 (SPG83), an autosomal recessive form of HSP. While HPDL variants are known to cause SPG83, the molecular mechanisms behind its role remains unclear, mostly due to rare nature of the condition. METHODS: The primary objective was to identify the genetic cause of HSP in two Iranian consanguineous families. Whole-exome sequencing (WES) was employed to identify genetic variants in the probands. Molegro Virtual Docker (MVD), a cutting-edge integrated platform, was utilized to perform protein-ligand docking simulations. This approach aimed to characterize the structural and functional consequences of the identified variants associated with SPG83 pathogenicity. RESULTS: WES identified two biallelic variants in HPDL: c.3G > C, a start-loss variant abolishing the canonical initiation codon, and c.128G > C, a missense variant. The c.128G > C variant is novel and is documented here for the first time in an SPG83 patient. Trio-based co-segregation analysis confirmed inheritance of variants. Furthermore, a comprehensive literature review revealed a significant consanguinity rate (49.55%) within families harboring HPDL variants. CONCLUSION: This study expands the genetic and clinical spectrum of HPDL variants. The identification of the genetic variants in the probands underscores the clinical value of genetic testing methods like WES as a valuable diagnostic tool.