Detection rates and phenotypic spectrum of m.3243A&gt;G in the MT-TL1 gene: A molecular diagnostic laboratory perspective

Chin, Judy; Marotta, Rosetta; Chiotis, Maria; Allan, Elizabeth; Collins, Steven J.

doi:10.1016/j.mito.2014.05.005

Cited by 27 publications

(21 citation statements)

References 42 publications

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“…We postulate that this could arise from differences in the threshold for biochemical expression of the variant allele between individuals, thus affecting negative selection against cells with high levels of the variant allele. This theory is compatible with the high level of variability in disease burden and phenotypic spectrum that is seen in individuals carrying m.3243A>G (Nesbitt et al, 2013), (Mancuso et al, 2014), (Kaufmann et al, 2011), (de Laat et al, 2012), (Chin et al, 2014), (Pickett et al, 2018) (Grady et al, 2018b).…”

Section: Discussionsupporting

confidence: 64%

Dynamics of the most common pathogenic mtDNA variant m.3243A>G demonstrate frequency-dependency in blood and positive selection in the germline

Fleischmann

Franco

et al. 2021

Preprint

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The A-to-G point mutation at position 3243 in the human mitochondrial genome (m.3243A>G) is the most common pathogenic mtDNA variant responsible for disease in humans. It is widely accepted that m.3243A>G levels decrease in blood with age, and correction representing ~2% annual decline is often applied to account for this change in mutation level. Here we report that recent data indicate the dynamics of m.3243A>G are far more complex and depend on the blood mutation level in a bi-phasic way. As a consequence, the traditional 2% correction, which is adequate on 'average', creates opposite predictive biases at high and low mutation levels. Thus, overall accuracy of traditional correction depends on the proportion of individuals with high and low mutant levels in the dataset. Unbiased age correction is needed to circumvent these drawbacks of the standard model. We propose to abolish both biases by using an approach where correction depends on mutation level in biphasic way, to account for the biphasic dynamics of m.3243A>G in blood. The significance of removing bias was further tested using germline selection as a model, in which we detected mutation patterns consistent with the possibility of positive selection for m.3243A>G. We conclude that use of bi-phasic approach will greatly improve the predictive accuracy of modeling data for changes in mtDNA mutations in the germline and in somatic cells during aging.

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Section: Discussionsupporting

confidence: 64%

Dynamics of the most common pathogenic mtDNA variant m.3243A>G demonstrate frequency-dependency in blood and positive selection in the germline

Fleischmann

Franco

et al. 2021

Preprint

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“…stature is another common feature in m.3243A> G mutation carriers, which may be partially related to growth hormone deficiency. 7 Cardiovascular involvement. Cardiac manifestations in m.3243A>G mutation patients are common and serious.…”

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confidence: 99%

“…27 Hearing impairment is one of the most common clinical features of mitochondrial disease, accounting for 62.8% of m.3243A>G mutation carriers. 7 The Newcastle group studied 238 m.3243A>G mutation patients found that up to 81% of patients had hearing impairment. 12 Hearing impairment may present alone or as a symptom of syndromic MIDD and MELAS syndrome.…”

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confidence: 99%

The non-syndromic clinical spectrums of mtDNA 3243A>G mutation

Shen

2021

NSJ

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The m.3243A >G mutation in the tRNA Leu )UUR( gene )MT-TL1( of the mitochondrial DNA is the most widely seen pathogenic mtDNA mutation which has major phenotypic variations. The clinical phenotype involves various organs such as the brain and nerves, skeletal muscles, heart, endocrine system, gastrointestinal tract, and skin. Some phenotypes conform to well established syndromes, while most of the symptoms appear individually or concomitant to other syndromes, making identification difficult. Furthermore, some progress has been made on cardiac manifestations as well as complications during pregnancy and perinatal period. This article provides a systematic review of the non-syndromic phenotypes and latest developments in m.3243A>G mutation.

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“…The prevalence of seizures ranged from 9% to 20% in adults. [ 23 24 ] In MELAS patients, recurrent stroke-like episodes were more frequent in those with m.3243A>G mutation than those without the mutation. [ 25 26 ] We found stroke-like episodes in 22% patients, higher than the prevalence from patients with mitochondrial mutations other than m.3243A>G mutation.…”

Section: Discussionmentioning

confidence: 99%

Clinical and Molecular Characteristics in 100 Chinese Pediatric Patients with m.3243A>G Mutation in Mitochondrial DNA

Xia

Liu

et al. 2016

Chinese Medical Journal

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Background:Mitochondrial diseases are a group of energy metabolic disorders with multisystem involvements. Variable clinical features present a major challenge in pediatric diagnoses. We summarized the clinical spectrum of m.3243A>G mutation in Chinese pediatric patients, to define the common clinical manifestations and study the correlation between heteroplasmic degree of the mutation and clinical severity of the disease.Methods:Clinical data of one-hundred pediatric patients with symptomatic mitochondrial disease harboring m.3243A>G mutation from 2007 to 2013 were retrospectively reviewed. Detection of m.3243A>G mutation ratio was performed by polymerase chain reaction (PCR)-restriction fragment length polymorphism. Correlation between m.3243A>G mutation ratio and age was evaluated. The differences in clinical symptom frequency of patients with low, middle, and high levels of mutation ratio were analyzed by Chi-square test.Results:Sixty-six patients (66%) had suffered a delayed diagnosis for an average of 2 years. The most frequent symptoms were seizures (76%), short stature (73%), elevated plasma lactate (70%), abnormal magnetic resonance imaging/computed tomography (MRI/CT) changes (68%), vomiting (55%), decreased vision (52%), headache (50%), and muscle weakness (48%). The mutation ratio was correlated negatively with onset age (r = −0.470, P < 0.001). Myopathy was more frequent in patients with a high level of mutation ratio. However, patients with a low or middle level of m.3243A>G mutation ratio were more likely to suffer hearing loss, decreased vision, and gastrointestinal disturbance than patients with a high level of mutation ratio.Conclusions:Our study showed that half of Chinese pediatric patients with m.3243A>G mutation presented seizures, short stature, abnormal MRI/CT changes, elevated plasma lactate, vomiting, and headache. Pediatric patients with these recurrent symptoms should be considered for screening m.3243A>G mutation. Clinical manifestations and laboratory abnormalities should be carefully monitored in patients with this point mutation.

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Detection rates and phenotypic spectrum of m.3243A>G in the MT-TL1 gene: A molecular diagnostic laboratory perspective

Cited by 27 publications

References 42 publications

Dynamics of the most common pathogenic mtDNA variant m.3243A>G demonstrate frequency-dependency in blood and positive selection in the germline

Dynamics of the most common pathogenic mtDNA variant m.3243A>G demonstrate frequency-dependency in blood and positive selection in the germline

The non-syndromic clinical spectrums of mtDNA 3243A>G mutation

Clinical and Molecular Characteristics in 100 Chinese Pediatric Patients with m.3243A>G Mutation in Mitochondrial DNA

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