Department of Obstetrics and Gynecology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China.
Department of Emergency, Luzhou Maternal and Child Health and Family Planning Service Center, Luzhou, 646000, China.
Ir J Med Sci. 2022 Apr;191(2):749-758. doi: 10.1007/s11845-021-02620-4. Epub 2021 Apr 11.
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.
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.
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 tRNA (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.
Our study indicates that mitochondrial ND1 T3394C mutation is involved in the pathogenesis of maternally inherited T2DM in these families.
线粒体 DNA (mtDNA) 突变与 2 型糖尿病 (T2DM) 有关。然而，这些突变在 T2DM 中的分子发病机制仍知之甚少。
本研究报道了两个汉族母系遗传 T2DM 家系的分子特征。这些母系亲属正在接受临床、生化、遗传评估和分子分析。此外，通过 PCR-Sanger 测序筛选这些母系亲属的整个线粒体基因组。
这些参与者的 T2DM 发病年龄从 28 岁到 71 岁不等，平均为 43 岁。线粒体基因组的分子分析在两个家系中均发现存在 ND1 T3394C 突变，以及属于线粒体单倍群 Y2 和 M9a 的一系列变体。m.T3394C 突变定位于 ND1 第 30 位非常保守的酪氨酸，可能导致 ND1 mRNA 代谢失败，导致线粒体功能障碍。此外，家系 1 中母系亲属的序列分析确定了 m.A14693G 突变，该突变发生在 tRNA（位置 54）的 TΨC 环中，对该 tRNA 的结构形成和稳定至关重要。因此，m.A14693G 突变可能导致 tRNA 代谢受损，从而加重由 ND1 T3394C 突变引起的线粒体功能障碍。然而，在家系 2 中未发现功能性 mtDNA 变体，这表明线粒体单倍群可能在糖尿病表达中不起重要作用。
我们的研究表明，线粒体 ND1 T3394C 突变参与了这些家系中母系遗传 T2DM 的发病机制。
