Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • DBIBB Variants of NEIL were also analysed in Primary

    2022-06-24

    Variants of NEIL1 were also analysed in Primary sclerosing cholangitis (PSC) and cholangiocarcinoma (CCA) patients by Forsbring et al. to identify effect of variants on these diseases. Four variants were identified i.e., one earlier validated (G83D) and three novel (E181K, H275, R339W). E181K was found in PSC, H275 in PSC-CCA and R339W in healthy individuals. G83D mutant protein was found to have highly reduced activity for 8oxoG, Tg and DHT in duplex DNA while no activity in single stranded DNA. It did not showed any change in activity towards 5ohC and 5ohU substrate in both double and single stranded DNA but δ-elimination activity was observed to be decreased for G83D mutant protein (Forsbring et al., 2009). Another study identified three novel SNPs (c.-3769C>T, c.-3170T>G, and c.-2681TA (Shibutani et al., 1991)) in promoter region in gastric cancer patients of Japan. Eighty patients were screened for presence of polymorphisms c.-3769C>T, c.-3170T>G, and c.-2681TA (Shibutani et al., 1991) and were found to have allele frequency of 0.6%, 9.4%, and 4.4%, respectively. These were then analyzed with Genomatix software to detect any transcription factor that binds the region containing these SNPs. Interestingly, c.-3170T>G was found to bind to the GATA binding transcription factors. The variant c.-3769G was predicted to disrupt the binding site for that transcription factor. Variant c.-2681TA (Shibutani et al., 1991) was predicted to interact with GZF1, TATA-binding protein and LIM factors but not found to disrupt the binding site (Goto et al., 2010). Another case-only study predicted SNP rs4462560 to be associated with reduced risk of acute radiation-induced esophageal toxicity (RIET) and radiation pneumonitis (RP). The GC/CC DBIBB was associated with lower risk of both grade≥2 RIET (adjusted hazard ratio [HR]=0.421; 95% confidence interval [CI]=0.207–0.856; P=0.017) and grade≥2 acute RP (adjusted HR=0.392; 95% CI=0.163–0.946 and P=0.037) but not with Overall Survival (adjusted HR=0.778; 95% CI=0.471–1.284; P=0.326). Other SNP rs7402844 did not show any significant association (Chen et al., 2013). Diabetes is a multifactorial systemic disease. Conditions like obesity, hypertension, hyperglycemia etc. causes metabolic syndrome that may be due to increased DNA damage in mitochondrial DNA and failure of NEIL1. Reports show that NEIL1 is involved in development of metabolic syndrome. Thus, mutations in this gene had also been linked to Type 2 Diabetes. In a case-control study of 70 patients with Type 2 diabetes and 50 healthy individuals, two NEIL1 mutations were detected in the patient group. One was A→G change (133A→G) at 133 position of the 8th exon. It was a silent mutation with frequency 2.9% and code for lysine only. Though it was not found to affect the protein structure or activity but it may involve in pathogenesis indirectly (Salmanoglu et al., 2012). Reports are also there for its association with autosomal recessive steroid-resistant nephrotic syndrome. A missense variant E181K was identified in NEIL1 using exome-sequencing. Total 247 healthy controls and 286 patients with nephrotic syndrome were screened. This mutation changes conserved sequence and thus affect its structure and may be a cause of nephrotic syndrome (Sanna-Cherchi et al., 2011). Interestingly, variant rs4462560 was genotyped in 284 patients and 353 controls to determine the association with keratoconus (KC) which is a degenerative corneal disorder. But no significant association of KC was found with this polymorphism. Thus, the variant may not be responsible for the risk of KC (Wojcik et al., 2014). Of the many polymorphisms that have been identified few have been characterized and found to affect NEIL1 function. The SNPs which have been characterized are mostly non-synonymous SNPs and of which G83D was reported to be the most damaging. G83 and S82 are present in the vicinity of the methionine residue at position 81which is the gap-filling residue. M81 along with other two residues, phenylalanine and arginine fill the gap formed due to the removal of damaged base and stabilizes the removed base. G83 is present at the tip of β sheet 5-strand towards N-terminal (Roy et al., 2007, Prakash et al., 2014). Thus, G83 and S82 may involve in the formation of active environment for gap filling. ΔE28 resides in β sheet-strand 1 (Fig. 6).