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Calreticulin novel mutations in type 2 diabetes mellitus

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Abstract

Imbalance in Ca2+ concentration and dysfunction of the chaperone system are linked with type 2 diabetes mellitus (T2DM). Two-dimensional protein profiling of pancreatic beta cells in T2DM subjects has shown that the Ca2+ binding chaperone, calreticulin (CALR), plays a role in the pathophysiology of this disease. In a case/control study, we performed mutation screening of the promoter region, 9 exons, and exon/intron boundaries of CALR by PCR-SSCP and sequencing in 120 patients with T2DM and 530 controls. Two novel mutations with an estimated frequency of 0.0005 were detected in T2DM patients, which were absent in the control pool (Mid P exact <0.01). The first mutation was a G>T transversion in intron 2 conserved polypurine tract at IVSII-142. The second mutation was a 9-bp deletion in the highly conserved exon 9 encompassing amino acids 397–399. To our knowledge, the current study reports for the first time, that CALR gene mutations that occur with T2DM. Studying larger groups of patients with T2DM for the CALR gene as well as other genes in the chaperone system is warranted to further elucidate the role of low frequency mutations in the causation of this complex disorder.

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Abbreviations

CALR:

Calreticulin

ER:

Endoplasmic reticulum

GLUT-1:

Glucose transporter 1 (GLUT-1

HBA1c:

Nonenzymatic glycosylated hemoglobin

SSCP:

Single strand conformation polymorphism analysis

T2DM:

Type 2 diabetes mellitus

UPR:

Unfolded protein response

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Acknowledgments

We wish to thank Staff of the BoAli clinical laboratory in Zanjan and Dr Faranak Sharifi for providing us with the clinical samples and Dr Javad Naserian was involved in statistical analysis. We would like to thanks Dr Amir Hosein Taromchi was involved in molecular genetics analysis and study design.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Authors’ contributions

SM was involved in study design, carried out molecular genetics and statistical analysis, compiled the data, wrote the Ms.

MR and KP were involved in data analysis.

MO was the principal geneticist and coordinator of the project, involved in conceptualization of the project, study design, oversee complete genetic analysis in laboratory, critical inputs and finalization of the manuscript.

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Authors and Affiliations

  1. Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran

    Sanaz Mahmazi & Kazem Parivar

  2. Department of Biology, Zanjan Branch, Islamic Azad University, Zanjan, Iran

    Mehdi Rahnema

  3. Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran

    Mina Ohadi

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  1. Sanaz Mahmazi
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  2. Kazem Parivar
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  4. Mina Ohadi
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Correspondence to Sanaz Mahmazi.

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Mahmazi, S., Parivar, K., Rahnema, M. et al. Calreticulin novel mutations in type 2 diabetes mellitus. Int J Diabetes Dev Ctries 33, 219–225 (2013). https://doi.org/10.1007/s13410-013-0152-0

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  • DOI: https://doi.org/10.1007/s13410-013-0152-0

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