Rare Primary Mitochondrial DNA Mutations and Probable Synergistic Variants in Leber’s Hereditary Optic Neuropathy

Achilli, Alessandro; Iommarini, Luisa; Olivieri, Anna; Pala, Maria; Kashani, Baharak Hooshiar; Reynier, Pascal; Morgia, Chiara La; Valentino, Maria Lucia; Liguori, Rocco; Pizza, Fabio; Barboni, Piero; Sadun, Federico; Negri, Anna Maria De; Zeviani, Massimo; Dollfus, Hélène; Moulignier, Antoine; Ducos, Ghislaine; Orssaud, C.; Bonneau, Dominique; Procaccio, Vincent; Leo-Kottler, Beate; Fauser, Sascha; Wissinger, Bernd; Amati‐Bonneau, Patrizia; Torroni, Antonio; Carelli, Valerio

doi:10.1371/journal.pone.0042242

Cited by 84 publications

(66 citation statements)

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“…However, a stringent pathogenicity of such variants is often hard to establish. 3 In a considerable fraction of clinically clear-cut patients, no causative mtDNA mutation have been found; and with an additional pronounced sex-biased penetrance, the genetic etiology of LHON remains complex. 4 It has been suggested that the specific haplogroup background of genetically verified LHON patients has an influence on disease manifestation, 5 and several so-called secondary LHON-associated mtDNA variants have been claimed to play a role in penetrance and disease expression, though the significance of such variants still remains uncertain.…”

Section: Discussionmentioning

confidence: 99%

Prevalence and Genetics of Leber Hereditary Optic Neuropathy in the Danish Population

Rosenberg

Nørby

Schwartz

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. In Denmark, the occurrence of Leber hereditary optic neuropathy (LHON) has continuously been monitored since 1944. We provide here a summary of 70 years of data collection including registered lines and subjects by the end of 2012.METHODS. Affected individuals were identified from a national register of hereditary eye diseases at the National Eye Clinic (NEC), a tertiary low vision rehabilitation center for the entire Danish population. The assembling of LHON pedigrees was based on the reconstruction of published families and newly diagnosed cases from 1980 to 2012 identified in the files of NEC. Genealogic follow-up on the maternal ancestry of all affected individuals was performed to identify a possible relation to an already known maternal line. A full genotypic characterization of the nation-based LHON cohort is provided.RESULTS. Forty different lines were identified. The number of live affected individuals with a verified mitochondrial DNA mutation was 104 on January 1, 2013, which translates to a prevalence rate of 1:54,000 in the Danish population.CONCLUSIONS. Haplogroup distribution as well as mutational spectrum of the Danish LHON cohort do not deviate from those of other European populations. The genealogic follow-up reveals a relatively high turnover among families with approximately 15 newly affected families per century and the dying out of earlier maternal lines.

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Section: Discussionmentioning

confidence: 99%

Prevalence and Genetics of Leber Hereditary Optic Neuropathy in the Danish Population

Rosenberg

Nørby

Schwartz

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…1,10,[38][39][40][41] In addition, the m.3733G>A mutation was a rare mutation, as in the case of European origin. 17,18 In this cohort, the m.3635G>A mutation in the Chinese population appeared to be more common than European patients. 16,42 Furthermore, the m.3866T>C mutation was presented more in Asian than in European patients with LHON.…”

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confidence: 63%

“…[15][16][17] Thus, the MT-ND1 gene is proposed to be another hot spot for mutations associated with LHON. 18 However, the mutational spectrum and incidence in the MT- To further understand the pathophysiology of LHON, we performed the clinical and genetic analysis of 1281 Han Chinese probands (patient or member of the family that brings a family under study) with LHON.…”

Section: Methodsmentioning

confidence: 99%

“…23 The homoplasmy of the m.3460G>A, m.3635G>A, m.3733G>A, and m.3866T>C mutations in these subjects was determined as detailed previously. [15][16][17]19,24,25 The allelic frequencies in the MT-ND1 gene in 478 Chinese control subjects were determined by direct sequencing of PCR products as described above. For defining the mitochondrial haplogroups, fragments spanning the D-loop region were PCR amplified by using oligodeoxynucleotides corresponding to mtDNA at positions 15,811 to 775, from 28 probands carrying the m.3394T>C mutation.…”

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confidence: 99%

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MitochondrialND1Variants in 1281 Chinese Subjects With Leber's Hereditary Optic Neuropathy

Liang

Zhang

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The purpose of this study was to investigate the mutational incidence and spectrum of mitochondrial ND1 gene in subjects with Leber's hereditary optic neuropathy (LHON). METHODS.A cohort of 1281 Han Chinese probands and 478 control subjects underwent sequence analysis of mitochondrial (mt)DNA. Resultant variants were evaluated for evolutionary conservation, allelic frequencies, and structural and functional consequences. Respiratory complex activities were measured using lymphoblastoid cell lines derived from 25 probands carrying the mtDNA mutation and 3 controls.RESULTS. Mutational analysis identified 178 (70 missense and 108 silent) variants in the MT-ND1 gene. The incidences of known m.3460G>A, m.3635G>A, m.3733G>A, m.3866T>C, and m.3394T>C mutations were 1.33%, 0.86%, 0.08%, 0.55%, and 2.97%, respectively. Fifteen novel putative mutations were identified in 27 probands, translated into 2.1% cases of this cohort. The activity of complex I in mutant cell lines carrying one of putative mutations ranged from 66% to 76% of the average values in control cell lines, whereas activities of complexes II, III, and IV in mutant cells were comparable with those in controls. The low penetrances of optic neuropathy were observed in pedigrees carrying novel putative mutation(s). Moreover, mtDNAs in 101 probands carrying the MT-ND1 mutation(s) were widely dispersed among 15 Eastern Asian haplogroups. In particular, the occurrences of haplogroups M, M9, and M10 in patients carrying the ND1 mutations were higher than those in controls.CONCLUSIONS. These data demonstrated that the MT-ND1 gene is a hot spot for mutations associated with LHON. Our findings may provide valuable information for pathophysiology, management, and genetic counseling of LHON.Keywords: Leber's hereditary optic neuropathy, mitochondrial DNA, mutation, spectrum, ND1 gene L eber's hereditary optic neuropathy (LHON) is the most common mitochondrial disorder leading to severe visual impairment or even blindness by death of retinal ganglion cells, affecting children through adults. [1][2][3][4][5] In the majority of cases worldwide, LHON is due to one of three point mutations in the mitochondrial DNA (mtDNA) encoding three subunits of respiratory chain complex I (Nicotinamide adenine dinucleotide [NADH] dehydrogenase): m.3460G>A(MT-ND1), m.11778G>A(MT-ND4), and m.14484T>C(MT-ND6).5-10 These LHON-associated mtDNA mutations occurred in heteroplasmy (mixture of wild-type and mutated molecules) or homoplasmy (only mutated molecules). These three mutations account for approximately 90% of LHON pedigrees in some countries, whereas these mutations are only responsible for 38.3% and 46.5% cases in two large cohorts of Chinese Han subjects with LHON. 11,12 In particular, the incidences of the m.3460G>A mutation in two large cohorts of Chinese Han subjects with LHON and 159 Caucasian pedigrees with LHON were 0.44%, 2.11%, and 13%, respectively, 10-12 suggesting the variable incidence and spectrum of mtDNA mutations among the different ethnic origins.12-14 The ...

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“…Some cause a variable clinical manifestation, from vision loss to complex neurological disorders called LHON+ 2. There are also 18 candidate primary LHON mutations found only in a single family or in a single case (MITOMAP, http://www.mitomap.org).…”

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confidence: 99%

m.3635G>A mutation as a cause of Leber hereditary optic neuropathy

et al. 2014

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Over 90% of Leber's hereditary optic neuropathy (LHON) is caused by one of three mtDNA mutations (m.11778A>G, m.3460G>A, m.14484T>C). The remaining cases are due to rare mutations in different genes encoding subunits of the respiratory chain. The proband is a 17-year-old male with symptoms of optic nerve atrophy. No common LHON mutations were found, but detailed sequencing identified a rare, homoplasmic mutation m.3635G>A in the ND1 gene.

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Rare Primary Mitochondrial DNA Mutations and Probable Synergistic Variants in Leber’s Hereditary Optic Neuropathy

Cited by 84 publications

References 59 publications

Prevalence and Genetics of Leber Hereditary Optic Neuropathy in the Danish Population

Prevalence and Genetics of Leber Hereditary Optic Neuropathy in the Danish Population

MitochondrialND1Variants in 1281 Chinese Subjects With Leber's Hereditary Optic Neuropathy

m.3635G>A mutation as a cause of Leber hereditary optic neuropathy

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