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Background: CYP27B1 gene codes for 25-hydroxyvitamin D3 1-a-hydroxylase, an enzyme that catalyses the activation of vitamin D to the 1-a, 25 dihydroxyvitamin D3. The activity of this enzyme is altered by non-synonymous single nucleotide polymorphisms (nsSNPs) located within its gene. Such alterations consequently affect the synthesis of the active form of the hormone, 1-a, 25 dihydroxyvitamin D3, resulting in vitamin D deficiency or insufficiency.
Objective: We aimed to investigate the impact of nsSNPs in the CYP27B1 gene on the structure and/or function of 25-hydroxyvitamin D3 1-a-hydroxylase.
Methods: The pathogenic nsSNPs in the human CYP27B1 obtained from National Centre for Biotechnology Information (NCBI) were analysed for their structural and functional consequence using mutation analysis algorithms like Consurf, I-Mutant, and MutPred. The effects of the mutation on tertiary structure of the human CYP27B1 protein was predicted using SWISS-MODEL while STRING was used to investigate its protein–protein interaction.
Results: Out of 938 SNPs in the human CYP27B1 gene, 455 that are responsible for missense mutations in the protein were subjected to various prediction algorithms to identify the pathogenic variants. Out of 24 consensus pathogenic nsSNPs, our Consurf analysis showed that mutations at conserved positions T321, R389 and G125 will significantly alter the structure of human CYP27B1 protein. These mutations also alter the metal binding and result in intrinsic structural disorder. These consequently, alter the 3D structure of the protein and could impact its ability to interact with other proteins like Cytochrome P450, family 2, subfamily R, polypeptide 1; Cytochrome P450, family 24, subfamily A, polypeptide 1 and Vitamin D receptor, that are involved in vitamin D pathway, as revealed by STRING.
Conclusion: These nsSNPs could contribute to vitamin D deficiency and its associated pathological conditions.
Keywords: Polymorphisms, CYP27B1, Vitamin D, Mutation, Cancer, Diabetes