Mitochondrial DNA triplication and punctual mutations in patients with mitochondrial neuromuscular disorders

Mkaouar-Rebai, Emna; Felhi, Rahma; Tabebi, Mouna; Alila-Fersi, Olfa; Chamkha, Imen; Maâlej, M.; Ammar, Marwa; Kammoun, Fatma; Keskes, Leila; Hachicha, M.; Fakhfakh, Faiza

doi:10.1016/j.bbrc.2016.03.126

Cited by 4 publications

(2 citation statements)

References 35 publications

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“…Pathogenic mtDNA insertions, duplications or triplications have been occasionally reported as causing MIDs, either as large-scale [23] or small-scale [24] rearrangements. In a case of maternally inherited diabetes and deafness (MIDD) associated with a complex-I deficiency in fibroblasts, mtDNA sequencing revealed a heteroplasmic insertion of one or two cytosine residues in the coding region of the MT-ND6 gene (m.14535_14536insC or CC), leading to a premature stop codon [25].…”

Section: Insertions Duplications and Triplicationsmentioning

confidence: 99%

“…In a case of maternally inherited diabetes and deafness (MIDD) associated with a complex-I deficiency in fibroblasts, mtDNA sequencing revealed a heteroplasmic insertion of one or two cytosine residues in the coding region of the MT-ND6 gene (m.14535_14536insC or CC), leading to a premature stop codon [25]. A 9 bp triplication in the MT-CYTB gene was detected in an African patient with isolated mitochondrial myopathy [24]. In a patient with dilated cardiomyopathy, the causative mutation was a 15 bp duplication in the tRNA Pro gene [26].…”

Section: Insertions Duplications and Triplicationsmentioning

confidence: 99%

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Genetic Counselling for Maternally Inherited Mitochondrial Disorders

2017

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The aim of this review was to provide an evidence-based approach to frequently asked questions relating to the risk of transmitting a maternally inherited mitochondrial disorder (MID). We do not address disorders linked with disturbed mitochondrial DNA (mtDNA) maintenance, causing mtDNA depletion or multiple mtDNA deletions, as these are autosomally inherited. The review addresses questions regarding prognosis, recurrence risks and the strategies available to prevent disease transmission. The clinical and genetic complexity of maternally inherited MIDs represent a major challenge for patients, their relatives and health professionals. Since many of the genetic and pathophysiological aspects of MIDs remain unknown, counselling of affected patients and at-risk family members remains difficult. MtDNA mutations are maternally transmitted or, more rarely, they are sporadic, occurring de novo (~25%). Females carrying homoplasmic mtDNA mutations will transmit the mutant species to all of their offspring, who may or may not exhibit a similar phenotype depending on modifying, secondary factors. Females carrying heteroplasmic mtDNA mutations will transmit a variable amount of mutant mtDNA to their offspring, which can result in considerable phenotypic heterogeneity among siblings. The majority of mtDNA rearrangements, such as single large-scale deletions, are sporadic, but there is a small risk of recurrence (~4%) among the offspring of affected women. The range and suitability of reproductive choices for prospective mothers is a complex area of mitochondrial medicine that needs to be managed by experienced healthcare professionals as part of a multidisciplinary team. Genetic counselling is facilitated by the identification of the underlying causative genetic defect. To provide more precise genetic counselling, further research is needed to clarify the secondary factors that account for the variable penetrance and the often marked differential expressivity of pathogenic mtDNA mutations both within and between families.

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Section: Insertions Duplications and Triplicationsmentioning

confidence: 99%

Section: Insertions Duplications and Triplicationsmentioning

confidence: 99%

Genetic Counselling for Maternally Inherited Mitochondrial Disorders

2017

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The Association of Mitochondrial Copy Number With Sarcopenia in Adult Survivors of Childhood Cancer

McCastlain

Howell

Welsh

et al. 2021

JNCI: Journal of the National Cancer Institute

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Background Adult childhood cancer survivors are at risk for frailty, including low muscle mass and weakness (sarcopenia). Using peripheral blood (PB) mitochondrial DNA copy number (mtDNAcn) as a proxy for functional mitochondria, this study describes cross-sectional associations between mtDNAcn and sarcopenia among survivors. Methods Among 1,762 adult childhood cancer survivors (51.6% male; median age = 29.4 [IQR = 23.3-36.8] years), with a median of 20.6 years from diagnosis (IQR = 15.2-28.2), mtDNAcn estimates were derived from whole-genome sequencing. A subset was validated by quantitative polymerase chain reaction and evaluated cross-sectionally using multivariable logistic regression for their association with sarcopenia, defined by race-, age-, and sex-specific low lean muscle mass or weak grip strength. All statistical tests were 2-sided. Results The prevalence of sarcopenia was 27.0%, higher among females than males (31.5% vs. 22.9%; P < 0.001) and associated with age at diagnosis; 51.7% of survivors with sarcopenia were diagnosed ages 4-13 years (p = 0.01). Sarcopenia was most prevalent (39.0%) among central nervous system tumor survivors. Cranial radiation (OR = 1.84; 95% CI = 1.32-2.59) and alkylating agents (OR = 1.34; 95% CI = 1.04-1.72) increased, while glucocorticoids decreased odds (OR = 0.72; 95% CI = 0.56-0.93) of sarcopenia. mtDNAcn decreased with age (β=-0.81; P = 0.002), was higher among females (β = 9.23; P = 0.01) and among survivors with a C allele at mt.204 (β=-17.9; P = 0.02). In adjusted models, every standard deviation decrease in mtDNAcn increased the odds of sarcopenia 20% (OR = 1.20; 95% CI = 1.07-1.34). Conclusions While a growing body of evidence supports PB mtDNAcn as a biomarker for adverse health outcomes, this study is the first to report an association between mtDNAcn and sarcopenia among childhood cancer survivors.

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Premature Physiologic Aging as a Paradigm for Understanding Increased Risk of Adverse Health Across the Lifespan of Survivors of Childhood Cancer

Ness

Kirkland

Gramatges

et al. 2018

JCO

112

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The improvement in survival of childhood cancer observed across the past 50 years has resulted in a growing acknowledgment that simply extending the lifespan of survivors is not enough. It is incumbent on both the cancer research and the clinical care communities to also improve the health span of survivors. It is well established that aging adult survivors of childhood cancer are at increased risk of chronic health conditions, relative to the general population. However, as the first generation of survivors age into their 50s and 60s, it has become increasingly evident that this population is also at risk of early onset of physiologic aging. Geriatric measures have uncovered evidence of reduced strength and speed and increased fatigue, all components of frailty, among survivors with a median age of 33 years, which is similar to adults older than 65 years of age in the general population. Furthermore, frailty in survivors independently increased the risk of morbidity and mortality. Although there has been a paucity of research investigating the underlying biologic mechanisms for advanced physiologic age in survivors, results from geriatric populations suggest five biologically plausible mechanisms that may be potentiated by exposure to cancer therapies: increased cellular senescence, reduced telomere length, epigenetic modifications, somatic mutations, and mitochondrial DNA infidelity. There is now a critical need for research to elucidate the biologic mechanisms of premature aging in survivors of childhood cancer. This research could pave the way for new frontiers in the prevention of these life-changing outcomes.

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Mitochondrial DNA triplication and punctual mutations in patients with mitochondrial neuromuscular disorders

Cited by 4 publications

References 35 publications

Genetic Counselling for Maternally Inherited Mitochondrial Disorders

Genetic Counselling for Maternally Inherited Mitochondrial Disorders

The Association of Mitochondrial Copy Number With Sarcopenia in Adult Survivors of Childhood Cancer

Premature Physiologic Aging as a Paradigm for Understanding Increased Risk of Adverse Health Across the Lifespan of Survivors of Childhood Cancer

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