mtdna DNA mtdna tr- NALeu(UUR)]3243 A G mtdna m.3243a G 3310C T 16189T C mtdna R587.1 Q75 Q

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1 4752 * DNA mtdna tr- NALeu(UUR)]3243 A G mtdna m.3243a G 3310C T 16189T C mtdna R587.1 Q75 Q78 A 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 , 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: (2012) 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 mtDNA 1.5% 60% trna Leu(UUR) DNA 10~20 DNA 4mtDNA * jxlucywang@hotmail.com gumm@sjtu.edu.cn

2 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] 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 [21] 1 [trnaleu(uur)]3243 β ATP A G mtdna K + Ca 2+

3 4754 mtdna 4 3 [22] 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 A G 3098 C G 3302 A G 3606 A G C T 3200 T C 3303 C G 3618 T C C A 3205 C T 3310 C T 3688 G C T C 3206 C T 3316 G A 4164 A G A G 3243 A G 3394 T C 4200 A T T C 3250 T C 3398 T C 4216 T C T C 3251 A G 3399 A T 4833 A G G A 3252 A G 3421 G T 4833 C T A G 3254 C T 3423 G T 4917 A G T C 3256 C T 3426 A G 4973 T C [trnaleu(uur)]3243 A G I ± 0.080μmol/h/mg ± OGTT μmol/h/mg P = ATP GHb <6.1% ± pmol/ m ± pmol/105 P = A G mtdna 3310C T β OGTT T 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 C T Chen J [24] ± μmol/h/107 P = mtdna T16189C / meta 16189C mtdna 3310C T NIDDM [ OR % CI NADH 1 ND P=0.003] mtdna NIDDM n=3283 n=2176 meta (ρ0) HeLa mtdna OR %CI P= mtdna 3310C T DNA mtssb 16189C ± 0.475μmol/h/mg mtssb

4 C T C NIDDM Meta NIDDM mtdna Park 16819C NIDDM 4 References [1] Gerbitz KD, van den Ouweland JMW, Massen JA, et al. Mitochondrial diabetes mellitus: a review [J]. Biochimica et Biophysica Acta, 1995, 1271(1): [2] Van den Ouweland JM, Lemkes HH, Ruitenbeek W, et al. Mutation in Q10 (CoQl0) Suzuki S mitochondrion t-rnaleu(urr) gene in a large pedigree with maternally transmitted type II diabetes melitus and deafness [J]. Nat Genet, 1998 CoQl0 MIDD CoQl0 1992, 1 (5): MIDD [3] Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human [28] disease [J]. Nat Rev Genet, 2005, 6(5): C E B1 B [4] Petersen KF, Dufour S, Befroy D, et al. Impaired mitochondreial activity in the insulin-resistant offspring of patients with type 2 diabetes [29] [30] [J]. N Engl J Med, 2004, 350: Silva KC 1 II AT1 [5]. [M] Chen Zhu (Editor). Medical Genetics [M]. 1st Edition, Beijing: People's Medical Publishing House, August, 2005, 8 : [6] Guillausseau PJ, Massin P, Dubois-LaForgue D, et al. Maternally inherited diabetes and deafness: a multicenter study [J]. Ann Intern [31] Med, 2001, 134: [7] Maassen JA. Mitochondrial diabetes, diabetes and the thiamine-responsive megaloblastic anaemia syndrome and MODY-2: Diabetes [32] with common pathophysiology? [J]. Panminerva Med, 2002, 44: MIDD [8] Ohkubo K, Yamano A, Nagashima M, et al. Mitochondrial gene mutations in the trna (Leu (UUR)) region and diabetes: prevalence and [33] clinical phenotypes in Japan [J]. Clin Chem, 2001, 47: [9] Wallace DC. Mitochondrial diseases in man and mouse [J]. Science, 1999, 283: [10] Maassen JA, 'T Hart LM, Van Essen E, et al. Mitochondrial Diabetes: Molecular Mechanisms and Clinical Presentation [J]. Diabetes, 2004, 53 (Suppl 1): S [11] 'T Hart LM, Jansen JJ, Lemkes HH, et al. Heteroplasmy levels of a mitochondrial gene mutation associated with diabetes melllitus decrease in leucocyte DNA upon aging [J]. Hum Mutat, 1996, 7: trna Leu (URR)3243 A G [12] Ohkubo K, Yamano A, Nagashima M, et al. Mitochondrial gene mutations in the trna(leu(uur)) region and diabetes: prevalence and clinical phenotypes in Japan [J]. Clinical Chemistry, 2011, 47:9 [35] [13]. [J]., 2010, 16(2): mtdna Ma Li-jing, Xu Mian. Pathogenesis and treatment of diabetes mellitus caused by mitochondrial gene mutation [J]. Medical Recapitulate, / 2010, 16(2): [14] Kelley DE, He J, Menshikova EV, et al. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes [J]. Diabetes, 2002, 51:

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