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Nitric oxide synthase-2 (NOS2) gene polymorphism c.1832C>T (Ser608Leu) associated with nitrosative stress in Fanconi anaemia

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Abstract

Fanconi anemia (FA) occurs due to genomic instability with predisposition to bone marrow failure, phenotypic abnormalities and cancers. Though mutations in 22 genes leading to DNA repair defect have been identified, the cellular factor such as oxidative stress has also shown to be associated with FA. Nitrosative Stress (NS) is biochemically correlated to many oxidative stress related disorders and the NS as a pathological hallmark in FA has been so far overlooked. We carried out the study first time in Indian patients with FA with an objective to understand the role of NS in the pathogenesis of FA. The study was carried out in 70 FA subjects. The FA subjects were diagnosed by chromosomal breakage analysis. Molecular study was carried out by Next Generation Sequencing and Sanger sequencing. The 3-nitrotyrosine [3-NT] levels were estimated through enzyme-linked immuno-sorbent assay (ELISA) and the nitric oxide synthase genes- NOS1 (c.-420-34221G>A (rs1879417), c.-420-10205C>T (rs499776), c.4286+720G>C (rs81631)) and NOS2 (c.1823C>T (p. Ser608Leu) (rs2297518)) polymorphism were studied by direct sequencing. Chromosomal breakage analysis revealed a high frequency of chromosomal breaks (Mean chromosomal breakage—4.13 ± 1.5 breaks/metaphase) in 70 FA patients as compared to the control. Molecular studies revealed FANCA (58.34%), FANCG (18.34%) and FANCL (16.6%) complementation groups. The 3-nitrotyrosine [3-NT] levels showed to be significantly (p < 0.05) elevated in FA subjects when compared to the age match controls. Genotyping of the NOS2 gene c.1823C>T (p. Ser608Leu) (rs2297518), showed statistically significant (P < 0.05) association with FA. Elevated level of 3-NT is one of the cause of NS and NOS2 gene polymorphism associated with FA is an important target in the treatment regimen.

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Acknowledgements

We would like to thank patients for participating in our study. We also thank the paediatricians and hemato-oncologists for the clinical assessment of the FA patients.

Funding

This study was carried out from DST/SERB (Grant no. EEQ/2016/000510; B. R.V).

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Authors and Affiliations

  1. Department of Cytogenetics, ICMR-National Institute of Immunohematology, K. E. M. Hospital Campus, Parel, Mumbai, 400 012, Maharashtra, India

    Merin George, Avani Solanki, Purvi Mohanty, Somprakash Dhangar & Babu Rao Vundinti

  2. Department of Paediatric Haematology, Institute of Child Health and Hospital for Children, Chennai, India

    Aruna Rajendran

  3. Department of Paediatric Haematology, Oncology, Apollo Speciality Hospital, Chennai, India

    Sheila Mohan

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  1. Merin George
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  2. Avani Solanki
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Correspondence to Babu Rao Vundinti.

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The study was approved by Institution Ethics Committee for research on Human subjects of ICMR-National institute of Immunohematology.

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Informed written consent was obtained from all individual participants included in the study and in case of minors; informed written assent was taken from the parents.

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George, M., Solanki, A., Mohanty, P. et al. Nitric oxide synthase-2 (NOS2) gene polymorphism c.1832C>T (Ser608Leu) associated with nitrosative stress in Fanconi anaemia. Mol Biol Rep 48, 2519–2525 (2021). https://doi.org/10.1007/s11033-021-06293-1

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