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Clinical and molecular features of two diabetes families carrying mitochondrial ND1 T3394C mutation

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Abstract

Background

Mutations in mitochondrial DNA (mtDNA) are found to be associated with type 2 diabetes mellitus (T2DM). However, the molecular pathogenesis of these mutations in T2DM is still poorly understood.

Methods

In this study, we report here the molecular features of two Han Chinese families with maternally transmitted T2DM. The matrilineal relatives are undergoing clinical, biochemical, genetic evaluations, and molecular analysis. Furthermore, the entire mitochondrial genomes of these matrilineal relatives are screened by PCR-Sanger sequencing.

Results

The age at onset of T2DM of these participants varies from 28 to 71 years, with an average of 43 years. Molecular analysis of mitochondrial genomes identifies the existence of ND1 T3394C mutation in both families, together with sets of variants belonging to mitochondrial haplogroup Y2 and M9a. The m.T3394C mutation is localized at very conserved tyrosine at position 30 of ND1, may result the failure in ND1 mRNA metabolism, and lead to mitochondrial dysfunction. Moreover, sequence analysis of matrilineal relatives in Family 1 identifies the m.A14693G mutation which occurs in the TΨC-loop of tRNAGlu (position 54), and is critical to the structural formation and stabilization of this tRNA. Thus, m.A14693G mutation may cause the impairment in tRNA metabolism, thereby worsens the mitochondrial dysfunction caused by ND1 T3394C mutation. However, no functional mtDNA variants are identified in Family 2 which suggest that mitochondrial haplogroup may not play an important role in diabetes expression.

Conclusions

Our study indicates that mitochondrial ND1 T3394C mutation is involved in the pathogenesis of maternally inherited T2DM in these families.

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Data availability

The datasets used and/or analyzed during the current study were available from the corresponding author on reasonable request.

Abbreviations

mtDNA:

Mitochondrial DNA

T2DM:

Type 2 diabetes mellitus

MELAS:

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes

tRNA:

Transfer RNA

OXPHOS:

Oxidative phosphorylation

mt-tRNA:

Mitochondrial transfer RNA

BP:

Blood pressure

BMI:

Body mass index

PTA:

Pure tone audiometry

dB:

Decibel

HPLC:

High-performance liquid chromatography

FPG:

Fasting plasmic glucose

OGTT:

Oral glucose tolerance test

rCRS:

Revised Cambridge reference sequences

CI:

Conservation index

MFE:

Minimum free energy

LHON:

Leber’s hereditary optic neuropathy

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Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China

    Xiaohong You & Luowen Bi

  2. Department of Emergency, Luzhou Maternal and Child Health and Family Planning Service Center, Luzhou, 646000, China

    Xueming Huang

  3. Department of Obstetrics and Gynecology, South Hospital of Fujian Provincial Hospital, Fuzhou, 350007, China

    Rui Li, Lin Zheng & Changzheng Xin

Authors
  1. Xiaohong You
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  2. Xueming Huang
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  3. Luowen Bi
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  4. Rui Li
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  5. Lin Zheng
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  6. Changzheng Xin
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Contributions

Changzheng Xin designed the study, Xiaohong You and Xueming Huang collected the two pedigrees and controls, and performed the clinical examinations. Luowen Bi and Rui Li performed the molecular analysis of mtDNA genes; Lin Zheng analyzed the data. All authors have read and approved the manuscript.

Corresponding author

Correspondence to Changzheng Xin.

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This study was approved by the Ethics Committee of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University.

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The informed consent was obtained from each individual participating for this study.

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The authors declare no competing interests.

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You, X., Huang, X., Bi, L. et al. Clinical and molecular features of two diabetes families carrying mitochondrial ND1 T3394C mutation. Ir J Med Sci 191, 749–758 (2022). https://doi.org/10.1007/s11845-021-02620-4

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