4752 * 200025 DNA mtdna tr- NALeu(UUR)]3243 A G mtdna m.3243a G 3310C T 16189T C mtdna R587.1 Q75 Q78 A 1673-6273 2012 24-4752-05 Study on Mitochondrial Gene Mutation Associated with Diabetes Mellitus* WANG Jian, GU Ming-min (Department of Medical Genetics, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China) ABSTRACT: Mutations in mitochondrail DNA (mtdna) can lead to various genetic diseases, including diabetes mellitus. The most common mutation associated with mtdna mutation is trnaleu (UUR)] 3243 A G. This article describes the links between mtdna and diabetes mellitus, and makes an introduction of clinical characteristics and pathogenesis of diabetes mellitus, summarizes several mutational genetic loci associated with diabetes mellitus, and mainly introduces mutational sites m.3243a G 3310C T 16189T C associated with pathophysiology of maternally inherited diabetes. The authors believe that the study of genetic loci mutations provides new insights of diabetic pathogenesis and offers new directions for treatment of diabetes mellitus. Key words: Diabetes mellitus; Mitochondria; Gene mutation; Genetic disease; Pathogenesis Chinese Library Classification (CLC): R587.1, Q75, Q78 Article ID:1673-6273(2012)24-4752-05 Document code: A NIDDM [4] (WHO) β 1 In- sulin-dependent Diabetes Mellitus IDDM 2 Noninsulin-Dependent Diabetes Mellitus 1 NIDDM 60 [1] 1992 Van den Ouweland (mitochondria) [trnaleu(uur)]3243 A G (maternally inherited diabetes and deafness syndrome MIDD) [2] mtdna DNA mtdna 1 [3] 2 mtdna 1000 3mtDNA 1.5% 60% trna Leu(UUR) DNA 10~20 DNA 4mtDNA * 31071107 1989-07 E-mail jxlucywang@hotmail.com E-mail gumm@sjtu.edu.cn 2012-02-05 2012-02-28
4753 [14] mtdna NIDDM [5] OXPHOS 2 [15] NIDDM 2.1 OXPHOS NIDDM 1 2 β Guillausseau PJ [6] MIDD ATP 87% [16] 46% 10 Olmos PR [17] m.3243a>g 2 Dogan SA [18] [7] [trnaleu(uur)]3243 A G A3243G Tfam 5 mtdna MELAS 7~9 MELAS A3243G Ca 2+ [8] mtdna A3243G 38 A3243G Yoshino J Nature [9] mtdna A3243G mtdna mtdna Ca 2+ β mtd- 5mtDNA NA DNA ATP/ADP K + Ca 2+ [13] 6 10 100 7 mtdna 2 NIDDM 8 mtdna -- A3243G [19] β β 5kHz A3243G Per2Luc PERIOD2- [10] Alport β 0.7% [11] / 1.7 / ZT2 ZT14 OXPHOS β mtdna [20] 3 [12] A3243G mtdna 2.2 50 [21] 1 [trnaleu(uur)]3243 β ATP A G mtdna K + Ca 2+
4754 mtdna 4 3 [22] 1 2 3.1 m.3243a G 3 4 Lindroos MM [23] 2 - [18F] 1 Table 1 The mitochondrial gene mutation associated with diabetes melllitus (Locus) (Base pair) (Locus) (Base pair) (Locus) (Base pair) (Locus) (Base pair) 1310 C T 3260 A G 3434 A G 5301 A G 1438 G A 3264 A G 3460 G A 8344 A G 1520 T C 3271 T C 3537 A G 8381 A G 1888 G A 3290 T C 3593 T C 12026 A G 3098 C G 3302 A G 3606 A G 12153 C T 3200 T C 3303 C G 3618 T C 12258 C A 3205 C T 3310 C T 3688 G C 14577 T C 3206 C T 3316 G A 4164 A G 14693 A G 3243 A G 3394 T C 4200 A T 14709 T C 3250 T C 3398 T C 4216 T C 14783 T C 3251 A G 3399 A T 4833 A G 15182 G A 3252 A G 3421 G T 4833 C T 15954 A G 3254 C T 3423 G T 4917 A G 16189 T C 3256 C T 3426 A G 4973 T C - 2-15 [trnaleu(uur)]3243 A G I 5 0.191 ± 0.080μmol/h/mg 0.288 ± OGTT 1 3 0.113μmol/h/mg P = 0.0223 ATP GHb <6.1% 2 7 1.119 ± 0.344 pmol/105 3 13 m. 1.419 ± 0.378 pmol/105 P = 0.044 3243A G mtdna 3310C T β OGTT 2 1 2 3 3.3 16189T C β 2 3 Park KS [25] m. mtdna T16189C NIDDM 3243 A G β m.3243 A T C mtdna G NIDDM [26,27] β m.3243 A G NIDDM 2469 NIDDM 1205 3.2 3310C T Chen J [24] 2.871 ± 0.484 μmol/h/107 P = 0.0392 mtdna T16189C / 16189 2 meta 16189C mtdna 3310C T NIDDM [ OR 1.256 95% CI NADH 1 ND1 1.08-1.46 P=0.003] mtdna NIDDM n=3283 n=2176 meta (ρ0) HeLa mtdna OR 1.335 95%CI 1.18-1.51 P=0.000003 mtdna 3310C T DNA mtssb 16189C 2.468 ± 0.475μmol/h/mg mtssb
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