Mitochondria DNA polymorphisms are associated with susceptibility to endometriosis.
ABSTRACT Because energy production involves oxidative phosphorylation, mitochondria are major sources of reactive oxygen species in the cell. Recent findings indicate that mitochondrial DNA (mtDNA) variants may play a role in the etiology of certain autoimmune and chronic inflammatory diseases. The aim of this study was to investigate the possible association between mtDNA polymorphisms and susceptibility to endometriosis. This study included 198 patients with histologically confirmed endometriosis and 167 patients without endometriosis as controls. Common variants of mtDNA at nt10398 (A/G transition), nt13708 (G/A transition), and nt16189 (T/C transition) were detected using polymerase chain reaction. An association study was performed with a chi-square test and logistic regression analysis. The prevalence of the mtDNA nt16189 variant was higher in patients with endometriosis (46.0%, 91 of 198) than in controls (34.7%, 58 of 167) (p=0.030) with odds ratio (OR) of 1.98 (95% confidence interval [CI]: 1.04-3.78). A combination of the 10398 and 16189 variants was also associated with increased risk for endometriosis (OR=1.90, 95% CI: 1.13-3.18, p=0.015). These associations remained significant even after adjusting for age and body mass index. Our data strongly suggest that the mtDNA 16189 variants and the combination of mtDNA 16189 and 10398 variants increase susceptibility to endometriosis.
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ABSTRACT: Endometriosis is a chronic gynecological benign disease that shares several features similar to malignancy. Mitochondrial DNA (mtDNA) mutations have been reported in all most all types of tumors. However, it is not known as to whether mtDNA mutations are associated with endometriosis. We sequenced the entire mitochondrial genome of analogous ectopic and eutopic endometrial tissues along with blood samples from 32 advanced stage endometriosis patients to analyze the role of somatic and germ-line mtDNA variations in pathogenesis of endometriosis. All ectopic tissues were screened for tumor-specific mtDNA deletions and microsatellite instability (MSI). We also performed mtDNA haplogrouping in 128 patients and 90 controls to identify its possible association with endometriosis risk. We identified 51 somatic (novel: 31; reported: 20) and 583 germ-line mtDNA variations (novel: 53; reported: 530) in endometriosis patients. The A13603G, a novel missense mutation which leads to a substitution from serine to glycine at the codon 423 of ND5 gene showed 100% incidence in ectopic tissues. Interestingly, eutopic endometrium and peripheral leukocytes of all the patients showed heteroplasmy (A/G; 40-80%) at this locus, while their ectopic endometrium showed homoplasmic mutant allele (G/G). Superimposition of native and mutant structures of ND5 generated by homology modeling revealed no structural differences. Tumor-specific deletions and MSI were not observed in any of the ectopic tissues. Haplogrouping analysis showed a significant association between haplogroup M5 and endometriosis risk (P: 0.00069) after bonferroni correction. Our findings substantiate the rationale for exploring the mitochondrial genome as a biomarker for the diagnosis of endometriosis.PLoS ONE 07/2012; 7(7):e40668. DOI:10.1371/journal.pone.0040668 · 3.53 Impact Factor
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ABSTRACT: Genetic alterations and aberrant expression of 'mitochondrial membrane complex I' (MMC-I) underlies several complex human disorders, but no reports are documented to date in endometriosis. Sequencing of mitochondrially encoded MMC-I subunits revealed 72 mutations of which 2 missense (G10398A; A13603A/G) and 1 synonymous (T10400C) mutations showed higher prevalence in patients. Insilico functional analysis predicted the A13603A/G, a novel heteroplasmy as 'damaging variant'. Our results indicate higher endometriosis risk for haplotype '10398A/10400C/13603AG' and haplogroup 'N'. Immunohistochemical analysis revealed elevated MMC-I expression in eutopic endometria of patients compared to controls. In conclusion, MMC-I alterations may constitute an inheritable risk factor for endometriosis.Mitochondrion 05/2013; 13(6). DOI:10.1016/j.mito.2013.05.003 · 3.52 Impact Factor
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ABSTRACT: Mitochondrial DNA depletion syndrome (MDS) is usually a severe disorder of infancy or childhood, due to a reduced copy number of mtDNA molecules. MDS with only mild, nonspecific clinical manifestations and onset in adulthood has not been reported. A 47-year-old Caucasian female with short stature and a history of migraine, endometriosis, Crohn's disease, C-cell carcinoma of the thyroid gland, and a family history positive for mitochondrial disorder (2 sisters, aunt, niece), developed day-time sleepiness, exercise intolerance, and myalgias in the lower-limb muscles since age 46y. She slept 9-10 hours during the night and 2 hours after lunch daily. Clinical exam revealed sore neck muscles, bilateral ptosis, and reduced Achilles tendon reflexes exclusively. Blood tests revealed hyperlipidemia exclusively. Nerve conduction studies, needle electromyography, and cerebral and spinal magnetic resonance imaging were noninformative. Muscle biopsy revealed detached lobulated fibers with subsarcolemmal accentuation of the NADH and SDH staining. Realtime polymerase chain reaction revealed depletion of the mtDNA down to 9% of normal. MDS may be associated with a mild phenotype in adults and may not significantly progress during the first year after onset. In an adult with hypersomnia, severe tiredness, exercise intolerance, and a family history positive for mitochondrial disorder, a MDS should be considered.Neurology International 06/2013; 5(2):28-30. DOI:10.4081/ni.2013.e9