Analysis of association among clinical features and shorter leukocyte telomere length in mitochondrial diabetes with m.3243A>G mitochondrial DNA mutation

BMC Medical Genetics

Yu-Xiu Li¹  Hua-Bing Zhang¹  Zeng-Yi Li⁴  Jian-ping Xu¹  An-Li Tong¹  Shi Zhang²  Jian-Jun Ji³  Rui Min¹  Mei-Cen Zhou¹ 

[1] Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Beijing 100730, China;Metabolic Disease Hospital of Tianjin Medical University, Tianjin City 300000, China;Hongshan Traditional Chinese Medicine Hospital, Chifeng City 024076, Inner Mongolia, China;Nanyang City Center Hospital, Nanyang City 473003, Henan, China

关键词: Leukocyte telomere length;    Clinical features;    G mitochondrial DNA mutation;    m.3243A>;    Mitochondrial diabetes;   

Others  :  1230640
DOI  :  10.1186/s12881-015-0238-2

 received in 2014-10-28, accepted in 2015-09-30,  发布年份 2015

【 摘 要 】

Background

Mitochondrial diabetes is a kind of rare diabetes caused by monogenic mutation in mitochondia. The study aimed to summarize the clinical phenotype profiles in mitochondrial diabetes withm.3243A>G mitochondrial DNA mutation and to investigate the mechanism in this kind of diabetes by analyzing the relationship among clinical phenotypes and peripheral leukocyte DNA telomere length.

Methods

Fifteen patients with maternally inherited diabetes in five families were confirmed as carrying the m.3243A>G mitochondrial DNA mutation. One hundred patients with type 2 diabetes and one hundred healthy control subjects were recruited to participate in the study. Sanger sequencing was used to detect the m.3243A>G mitochondrial DNA mutation. The peak height G/A ratio in the sequence diagram was calculated. Real-time polymerase chain reaction (PCR) was used to measure telomere length.

Results

The patients with mitochondrial diabetes all had definite maternally inherited history, normal BMI (19.5 ± 2.36 kg/m ² ), early onset of diabetes (35.0 ± 14.6 years) and deafness. The peak height G/A ratio correlated significantly and negatively with the age at onset of diabetes (≦25 years, 61.6 ± 20.17 %; 25–45 years, 16.59 ± 8.64 %; >45 years, 6.37 ± 0.59 %; p = 0.000). Telomere length was significantly shorter among patients with mitochondrial diabetes and type 2 diabetes than in the control group (1.28 ± 0.54 vs. 1.14 ± 0.43 vs. 1.63 ± 0.61; p = 0.000). However, there was no significant difference between patients with mitochondrial diabetes and those with type 2 diabetes. There was no correlation between telomere length and the peak height G/A ratio.

Conclusion

Deafness with definite maternal inheritance and normal BMI, associated with elevated blood lactic acid and encephalomyopathy, for the most part, suggest the diagnosis of mitochondrial diabetes . The peak height G/A ratio could reflect the spectrum of age at onset of the disease. Telomere length was shorter in patients with mitochondrial diabetes and those with type 2 diabetes, which suggests that the shorter telomere length is likely involved in the pathogenesis of diabetes but is not specific for this kind of diabetes.

【 授权许可】

   
2015 Zhou et al.

【 图 表 】

Fig. 1.

Fig. 2.

【 参考文献 】

• [1]Goto Y-I, Nonaka I, Horai S. A mutation in the tRNA Leu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature. 1990; 348:651-3.
• [2]Chae JH, Hwang H, Lim BC, Cheong HI, Hwang YS, Kim KJ. Clinical features of A3243G mitochondrial tRNA mutation. Brain Dev. 2004; 26:459-62.
• [3]Verma A, Moraes C, Shebert R, Bradley W. A MERRF/PEO overlap syndrome associated with the mitochondrial DNA 3243 mutation. Neurology. 1996; 46:1334-6.
• [4]Van den Ouweland J, Lemkes H, Ruitenbeek W, Sandkujl L, de Vijlder M, Struyvenberg P et al.. Mutation in mitochondrial tRNA Leu(UUR) gene in a large pedigree with maternally transmitted Type 2 diabetes and deafness. Nat Genet. 1992; 1:368-71.
• [5]Naing A, Kenchaiah M, Krishnan B, Mir F, Charnley A, Egan C et al.. Maternally inherited diabetes and deafness (MIDD): Diagnosis and management. J Diabetes Complications. 2014; 28(4):542-6.
• [6]Maassen J, Janssen G, t’Hart LM. Molecular mechanisms of mitochondrial diabetes (MIDD). Ann Med. 2005; 37:213-21.
• [7]Zhao J, Miao K, Wang H, Ding H, Wang DW. Association between telomere length and type 2 diabetes mellitus: a meta-analysis. PLoS One. 2013; 8:e79993.
• [8]Harte AL, da Silva NF, Miller MA, Cappuccio FP, Kelly A, O'Hare JP et al.. Telomere length attrition, a marker of biological senescence, is inversely correlated with triglycerides and cholesterol in South Asian males with type 2 diabetes mellitus. Exp Diabetes Res. 2012; 2012:895185.
• [9]Zee RY, Castonguay AJ, Barton NS, Germer S, Martin M. Mean Leukocyte telomere length shortening and type 2 diabetes mellitus: a case–control study. Transl Res. 2010;155:166–9.
• [10]Salpea KD, Talmud PJ, Cooper JA, Maubaret CG, Stephens JW, Abelak K et al.. Association of telomere length with type 2 diabetes, oxidative stress and UCP2 gene variation. Atherosclerosis. 2010; 209:42-50.
• [11]Kurz DJ, Decary S, Hong Y, Trivier E, Akhmedov A, Erusalimsky JD et al.. Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells. J Cell Sci. 2004; 117:2417-26.
• [12]Liu L, Trimarchi JR, Smith PJ, Keefe DL. Mitochondrial dysfunction leads to telomere attrition and genomic instability. Aging Cell. 2002;1:40–6.
• [13]Passos JF, Saretzki G, von Zglinicki T. DNA damage in telomeres and mitochondria during cellular senescence: is there a connection? Nucleic Acids Res. 2007; 35:7505-13.
• [14]Cawthon RM. Telomere length measurement by a novel monochrome multiplex quantitative PCR method. Nucleic Acids Res. 2009; 37:e21.
• [15]Chinnery PF, Zwijnenburg P, Walker M, Howell N, Taylor R, Lightowlers RN et al.. Non-random tissue distribution of mutant mtDNA. Am J Med Genet. 1999; 85:498-501.
• [16]Narbonne H, Perucca-Lostanlen D, Desnuelle C, Vialettes B, Saunieres A, Paquis-Fluckinger V. Searching for A3243G mito-chondrial DNA mutation in buccal mucosa in order to improve the screening of patients with mitochondrial diabetes. Eur J Endocrinol. 2001; 145:541-2.
• [17]Wang S, Wu S, Zheng T, Yang Z, Ma X, Jia W et al.. Mitochondrial DNA mutations in diabetes mellitus patients in Chinese Han population. Gene. 2013; 531:472-5.
• [18]Mancuso M, Orsucci D, Angelini C, Bertini E, Carelli V, Comi GP et al.. The m.3243A>G mitochondrial DNA mutation and related phenotypes. A matter of gender? J Neurol. 2014; 261:504-10.
• [19]Zhang S, Tong AL, Zhang Y, Nie M, Li YX, Wang H. Heteroplasmy level of the mitochondrial tRNaLeu(UUR) A3243G mutation in a Chinese family is positively associated with earlier age-of-onset and increasing severity of diabetes. Chin Med Sci J. 2009; 24:20-5.
• [20]Kadowaki H, Tobe K, Mori Y, Sakura H, Sakuta R, Nonaka I et al.. Mitochondrial gene mutation and insulin-deficient type of diabetes mellitus. Lancet. 1993; 341:893-4.
• [21]Walker M, Taylor R, Stewart M, Bindoff L, Shearing P, Anyaoka V et al.. Insulin and proinsulin secretion in subjects with abnormal glucose tolerance and a mitochondrial tRNA Leu(UUR) mutation. Diabetes Care. 1995; 18:1507-9.
• [22]Steel KP, Kros CJ. A genetic approach to understanding auditory function. Nat Genet. 2001; 27:143-9.
• [23]Laloi-Michelin M, Meas T, Ambonville C. The clinical variability of maternally inherited diabetes and deafness is associated with the degree of heteroplasmy in blood leukocytes. J Clin Endocrinol Metab. 2009; 94:3025-30.
• [24]Wallace DC. Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science. 1992; 256:628-32.
• [25]Du M, Prescott J, Cornelis MC, Hankinson SE, Giovannucci E, Kraft P et al.. Genetic predisposition to higher body mass index or type 2 diabetes and leukocyte telomere length in the Nurses’ Health Study. PLoS One. 2013; 8:e52240.
• [26]Meas T, Laloi-Michelin M, Virally M, Ambonville C, Kevorkian JP, Guillausseau PJ. Mitochondrial diabetes: clinical features, diagnosis and management. Rev Med Interne. 2010; 31:216-21.