Genetic Susceptibility of Vitamin D Receptor Gene Polymorphisms on Autosomal Recessive Primary Microcephaly Patients in Pakistani Population: A Case-Control and In-Silico Study

Abstract

Abstract Background Autosomal recessive primary microcephaly (MCPH) is a rare genetic disorder that leads to reduced cerebral cortex caused by a mutation in corticogenesis. The expression of the Vitamin D receptor (VDR) gene is involved in the proliferation and differentiation of neural stem cells, and VDRpolymorphisms have been associated with various neurological disorders. However, their relationship with MCPH has not been explored. This study aimed to investigate the association of VDRpolymorphisms with MCPH and its In-silico analysis. Methods and Results Blood samples of 64 MCPH patients and 52 controls were collected to genotype VDR SNPs (TaqI (rs731236), FokI (rs2228570) and BsmI (rs1544410)) . In-silico tools were also used to assess the effects of exonic SNPs on mRNA and protein structure and pathogenicity of exonic and intronic SNPs. The study found that serum 25-OH vitamin D3 levels were significantly different in MCPH patients and healthy controls (P=0.000). The genetic analysis showed that VDRpolymorphisms of FokI and BsmI were seven times more frequent in MCPH patients than in controls (P<0.05) and the dominant model for TaqI and recessive model for BsmI polymorphisms were also associated with the pathogenesis of MCPH. In-silico analysis showed that the pathogenicity effects of rs2228570 and rs1544410 are neutral while rs731236 causes a silent mutation which has no effect on VDR protein. Conclusion VDR polymorphisms of FokI and BsmI are associated with the risk of MCPH. These findings suggest that VDR polymorphisms play a role in MCPH, which could provide important insights for understanding the molecular mechanisms of the disease.