The m.3244G&gt;A mutation in mtDNA is another cause of progressive external ophthalmoplegia

Sotiriou, Evangelia; Çoku, Jorida; Tanji, Kurenai; Huang, Huabin; Hirano, Michio; DiMauro, Salvatore

doi:10.1016/j.nmd.2009.01.014

Cited by 9 publications

(3 citation statements)

References 10 publications

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“…NC_012920.1:m.3244G > C) mutation This reported mutation was found associated with the novel missense p.M601L mutation in family 2. It should be noted that the m.3244G > A mutation in the tRNALeu(UUR) gene has already been observed in patients suffering from various diseases such as MELAS syndrome [19], chronic progressive external ophthalmoplegia [20], and Kearns-Sayre syndrome [21]. This recent nding adds to previously published research demonstrating that this mutation has pathogenic implications and correlates with the various diseases already mentioned.…”

Section: The Missense Mutationsupporting

confidence: 55%

Respiratory Chain Complex I Deficiency in Leber Hereditary Optic Neuropathy: Insights from Ophthalmologic and Molecular Investigations in Tunisia

Chkioua,

Amri,

Sahli

et al. 2024

Preprint

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Background Leber hereditary optic neuropathy (LHON) is a mitochondrial DNA (mtDNA) rare disease due to the mutation of the NADH dehydrogenase enzyme. LHON is characterized by a sudden central vision loss due to focal degeneration of the retinal ganglion cell layer and optic nerve. Symptoms usually appear between the age of 18 and 35 years. Some individuals present the mtDNA mutations but do not express this disease. The heteroplasmic or homoplasmic character of the mutations among patients explains why they develop the disease or not even though they carry the mutation. Methods This study was performed in collaboration with the department of ophthalmology of Farhat Hached Hospital, Sousse, Tunisia. Screening for the common mutations in ND1 gene (mt.3460G > A), ND4 gene (mt.11778G > A) and ND6 gene (mt.14484T > C) was performed in five Tunisian families by standard RFLP PCR, followed by direct sequencing of the entire of these genes. Indeed, bioinformatics tools were used to predict the potential functional impact of the identified mutations on the Human mitochondrial respiratory complex I protein. Results one novel p.Leu601Met (m.14137C > A), and four previously reported mutations were identified in this study including: rs199476112G > A (m.11778G > A); rs202227543G > A (m.14258G > A); m.3244G > C, rs1603224763 (m.14510 dup) and NC_012920.1:m.3244G > C. In this present report, only one patient was found carrying the primary point mutation (m.G11778A). The ophthalmologic findings showing major fundus changes included hyperemic optic discs; disc pseudo-oedema and microangiopathy leading to optic disc atrophy. The analyses of the stability of protein upon identified mutations using DynaMut tool server demonstrated that these variations induce a rigidification in the region where they are located. Conclusion This is the first Tunisian report of mtDNA mutations identified in Tunisia causing the LHON. The main factors involved in the pathophysiological mechanisms of this disease are genetic, epigenetic, hormonal and environmental influences.

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Section: The Missense Mutationsupporting

confidence: 55%

Respiratory Chain Complex I Deficiency in Leber Hereditary Optic Neuropathy: Insights from Ophthalmologic and Molecular Investigations in Tunisia

Chkioua,

Amri,

Sahli

et al. 2024

Preprint

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“…[9][10][11][12] In contrast, the m.3243A4G mutation causes several major clinical phenotypes of mitochondrial disease such as myopathy, encephalopathy, lactic acidosis, stroke-like episodes, maternally inherited diabetes and deafness, chronic progressive external ophthalmoplegia and mitochondrial diabetes. [31][32][33] However, epidemiological evidence of the prevalence of the patients with the m.3243A4G mutation in the population still has limitations. The patients with m.3243A4G including asymptomatic cases in the general population are thought to be as common as 6.57-16.3 per 100 000.…”

Section: Discussionmentioning

confidence: 99%

Extensive and rapid screening for major mitochondrial DNA point mutations in patients with hereditary hearing loss

et al. 2010

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Sensorineural hearing loss (HL) is one of the most frequent clinical features in patients with mitochondrial diseases caused by mitochondrial DNA (mtDNA) mutations, and hearing is impaired in over half of all cases with mitochondrial disorders. This study analyzed 373 patients with suspected hereditary HL using an extensive and rapid suspension-array screening system for 29 major mtDNA mutations, including the m.1555A4G homoplasmic mutation in the MT-RNR1 gene, which causes non-syndromic sensorineural HL and aminoglycoside-induced HL, and the m.3243A4G heteroplasmic mutation in the MT-TL1 gene. This method is rapid and suitable for large-scale screening because universal 96-well plates are available for use, and because an analysis of each plate can be completed within 1 h. This system detected five different mtDNA mutations in 24 of the 373 (6.4%) patients. The m.1555A4G and m.3243A4G mutations were detected in 11 (2.9%) and 9 (2.7%) patients, respectively. In addition, three mutations, that is, m.8348A4G in the MT-TK gene, m.11778G4A in the MT-ND4 gene and 15498G4A in the MT-CYB gene were detected in one patient for each. This screening system is useful for the genetic diagnosis and epidemiological study of both syndromic and non-syndromic HL.

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“…Carriers of m.3243A>G are clinically heterogeneous. Their phenotypes constitute a broad spectrum ranging from asymptomatic to being affected by one of the several diseases, such as maternally inherited diabetes and deafness (MIDD) (van den Ouweland et al, 1992), chronic progressive external ophthalmoplegia (CPEO) (Sotiriou et al, 2009) and MELAS syndrome.…”

Section: Introductionmentioning

confidence: 99%

Molecular and neurological features of MELAS syndrome in paediatric patients: A case series and review of the literature

Seed

Dean

Krishnakumar

et al. 2022

Molec Gen & Gen Med

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Background Mitochondrial encephalomyopathy, lactic acidosis and stroke‐like episodes (MELAS) syndrome is one of the most well‐known mitochondrial diseases, with most cases attributed to m.3243A>G. MELAS syndrome patients typically present in the first two decades of life with a broad, multi‐systemic phenotype that predominantly features neurological manifestations––stroke‐like episodes. However, marked phenotypic variability has been observed among paediatric patients, creating a clinical challenge and delaying diagnoses. Methods A literature review of paediatric MELAS syndrome patients and a retrospective analysis in a UK tertiary paediatric neurology centre were performed. Results Three children were included in this case series. All patients presented with seizures and had MRI changes not confined to a single vascular territory. Blood heteroplasmy varied considerably, and one patient required a muscle biopsy. Based on a literature review of 114 patients, the mean age of presentation is 8.1 years and seizures are the most prevalent manifestation of stroke‐like episodes. Heteroplasmy is higher in a tissue other than blood in most cases. Conclusion The threshold for investigating MELAS syndrome in children with suspicious neurological symptoms should be low. If blood m.3243A>G analysis is negative, yet clinical suspicion remains high, invasive testing or further interrogation of the mitochondrial genome should be considered.

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The m.3244G>A mutation in mtDNA is another cause of progressive external ophthalmoplegia

Cited by 9 publications

References 10 publications

Respiratory Chain Complex I Deficiency in Leber Hereditary Optic Neuropathy: Insights from Ophthalmologic and Molecular Investigations in Tunisia

Respiratory Chain Complex I Deficiency in Leber Hereditary Optic Neuropathy: Insights from Ophthalmologic and Molecular Investigations in Tunisia

Extensive and rapid screening for major mitochondrial DNA point mutations in patients with hereditary hearing loss

Molecular and neurological features of MELAS syndrome in paediatric patients: A case series and review of the literature

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