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Screening of OTULIN gene mutation with targeted next generation sequencing in Turkish populations and in silico analysis of these mutations

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Abstract

Background

OTULIN-related autoinflammatory syndrome (ORAS) is an autosomal recessive disease characterized by systemic inflammation, recurrent fever. Due to limited knowledge about the OTULIN DNA variants that cause ORAS, the diagnosis and treatment of this disease is difficult. In this study, we aim to identify OTULIN DNA variants responsible for the genetic pathology of ORAS and observe the effects of these variants on the OTULIN protein structure and the function with different bioinformatics approaches.

Methods

The present study included 3230 individuals with the suspicion of an autoinflammatory disease who were referred to Ege University Children’s Hospital Molecular Medicine Laboratory. OTULIN variants were detected using a panel consisting of 37 different autoinflammatory diseases (AID) genes via targeted Next-Generation Sequencing.

Results

As a result of the study, DNA variants associated with various AID were detected in 65% of the individuals to whom the panel was applied. Among these variants, only three different OTULIN variants (p.Val82Ile, p.Gln115His and p.Leu131_Arg132insLeuCysThrGlu) were detected. The pathogenic effects of the variants detected in the OTULIN gene were determined by using Polyphen2 as “Probably Pathogenic” for the p.Val82Ile and “benign” for the p.Gln115His. At the same time, the effects of these variants on the structure and function of the OTULIN protein were investigated by in silico approaches. Both variants reduce protein stability and binding affinity.

Conclusion

The results of the current study suggest that the evaluation of OTULIN variants with in silico approaches will contribute to the development of personalized treatments by diagnosing the disease specific to the variant.

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Abbreviations

ORAS:

OTULIN-Related autoinflammatory syndrome

Met1-Ub:

Met1-linked polyubiquitin

LUBAC:

Linear ubiquitin chain assembly complex

NF-kB:

Nuclear factor kappa B

IKB:

NF-kB inhibitor kabba-B

DUB:

Deubiquitinase

OTU-cat:

Catalytic OTU domain

AID:

Autoinflammatory diseases

NGS:

Next generation sequencing

SA:

Solvent accessibility

VDW:

Van Der Walls

EE:

Electrostatic energy

BSA:

Buried surface area

HGMD:

Human gene mutation database

ACMG:

The American College of Medical Genetics and Genomics

PDB:

Protein Data Bank

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Funding

No funding was obtained for this study.

Author information

Authors and Affiliations

  1. Molecular Medicine Laboratory, Ege University School of Medicine, Izmir, Turkey

    Yüksel Gezgin, Berkay Kırnaz & Afig Berdeli

  2. Department of Pediatric Rheumatology, Faculty of Medicine, Ege University, Izmir, Turkey

    Afig Berdeli

Authors
  1. Yüksel Gezgin
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  2. Berkay Kırnaz
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  3. Afig Berdeli
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Contributions

YG and BK the manuscript preparation and all data analysis. AB and YG the experiment design, selection study group and AB. collection samples from patients. All authors reviewed the manuscript.

Corresponding author

Correspondence to Yüksel Gezgin.

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Competing interests

The authors declare no competing interests.

Ethical approval

Ethical approval was provided from the Ethics committee of Ege University, Izmir, Turkey (21-12. /IT/20). This study was conducted in accordance with the Helsinki Ethical Standards.

Informed consent

Since it was a retrospective study based on archive scanning, informed consent to participate was not obtained from the subjects. We recalled the patients with the OTULIN mutation and informed consent was obtained from these patients. The informed consent was granted by the parents/LAR of the children in the study. The ages of the subjects in this study ranged from 2 months to 18 years old.

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Gezgin, Y., Kırnaz, B. & Berdeli, A. Screening of OTULIN gene mutation with targeted next generation sequencing in Turkish populations and in silico analysis of these mutations. Mol Biol Rep 49, 4643–4652 (2022). https://doi.org/10.1007/s11033-022-07312-5

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  • DOI: https://doi.org/10.1007/s11033-022-07312-5

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