Cybrid studies establish the causal link between the mtDNA m.3890G>A/MT-ND1 mutation and optic atrophy with bilateral brainstem lesions

Leonardo Caporali, Anna Maria Ghelli, Luisa Iommarini, Alessandra Maresca, Maria Lucia Valentino, Chiara La Morgia, Rocco Liguori, Claudia Zanna, Piero Barboni, Vera De Nardo, Andrea Martinuzzi, Giovanni Rizzo, Caterina Tonon, Raffaele Lodi, Maria Antonietta Calvaruso, Martina Cappelletti, Anna Maria Porcelli, Alessandro Achilli, Maria Pala, Antonio Torroni & 1 others Valerio Carelli

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12 Citations (Scopus)

Abstract

Complex I (CI) deficiency is a frequent cause of mitochondrial disorders and, in most cases, is due to mutations in CI subunit genes encoded by mitochondrial DNA (mtDNA). In this study, we establish the pathogenic role of the heteroplasmic mtDNA m.3890G>A/. MT- ND1 (p.R195Q) mutation, which affects an extremely conserved amino acid position in ND1 subunit of CI. This mutation was found in a young-adult male with optic atrophy resembling Leber's hereditary optic neuropathy (LHON) and bilateral brainstem lesions. The only previously reported case with this mutation was a girl with fatal infantile Leigh syndrome with bilateral brainstem lesions. Transfer of the mutant mtDNA in the cybrid cell system resulted in a marked reduction of CI activity and CI-dependent ATP synthesis in the presence of a normally assembled enzyme.These findings establish the pathogenicity of the m.3890G>A/. MT- ND1 mutation and remark the link between CI mutations affecting the mtDNA-encoded ND subunits and LHON-like optic atrophy, which may be complicated by bilateral and symmetric lesions affecting the central nervous system. Peculiar to this mutation is the distribution of the brainstem lesions, with sparing of the striatum in both patients.

LanguageEnglish
Pages445-452
Number of pages8
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1832
Issue number3
Early online date14 Dec 2012
DOIs
Publication statusPublished - 1 Mar 2013
Externally publishedYes

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Optic Atrophy
Mitochondrial DNA
Brain Stem
Mutation
Leber's Hereditary Optic Atrophy
Leigh Disease
Mitochondrial Diseases
Virulence
Young Adult
Central Nervous System
Adenosine Triphosphate
Amino Acids
Enzymes
Genes

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Caporali, Leonardo ; Ghelli, Anna Maria ; Iommarini, Luisa ; Maresca, Alessandra ; Valentino, Maria Lucia ; La Morgia, Chiara ; Liguori, Rocco ; Zanna, Claudia ; Barboni, Piero ; De Nardo, Vera ; Martinuzzi, Andrea ; Rizzo, Giovanni ; Tonon, Caterina ; Lodi, Raffaele ; Calvaruso, Maria Antonietta ; Cappelletti, Martina ; Porcelli, Anna Maria ; Achilli, Alessandro ; Pala, Maria ; Torroni, Antonio ; Carelli, Valerio. / Cybrid studies establish the causal link between the mtDNA m.3890G>A/MT-ND1 mutation and optic atrophy with bilateral brainstem lesions. In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 2013 ; Vol. 1832, No. 3. pp. 445-452.
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abstract = "Complex I (CI) deficiency is a frequent cause of mitochondrial disorders and, in most cases, is due to mutations in CI subunit genes encoded by mitochondrial DNA (mtDNA). In this study, we establish the pathogenic role of the heteroplasmic mtDNA m.3890G>A/. MT- ND1 (p.R195Q) mutation, which affects an extremely conserved amino acid position in ND1 subunit of CI. This mutation was found in a young-adult male with optic atrophy resembling Leber's hereditary optic neuropathy (LHON) and bilateral brainstem lesions. The only previously reported case with this mutation was a girl with fatal infantile Leigh syndrome with bilateral brainstem lesions. Transfer of the mutant mtDNA in the cybrid cell system resulted in a marked reduction of CI activity and CI-dependent ATP synthesis in the presence of a normally assembled enzyme.These findings establish the pathogenicity of the m.3890G>A/. MT- ND1 mutation and remark the link between CI mutations affecting the mtDNA-encoded ND subunits and LHON-like optic atrophy, which may be complicated by bilateral and symmetric lesions affecting the central nervous system. Peculiar to this mutation is the distribution of the brainstem lesions, with sparing of the striatum in both patients.",
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Caporali, L, Ghelli, AM, Iommarini, L, Maresca, A, Valentino, ML, La Morgia, C, Liguori, R, Zanna, C, Barboni, P, De Nardo, V, Martinuzzi, A, Rizzo, G, Tonon, C, Lodi, R, Calvaruso, MA, Cappelletti, M, Porcelli, AM, Achilli, A, Pala, M, Torroni, A & Carelli, V 2013, 'Cybrid studies establish the causal link between the mtDNA m.3890G>A/MT-ND1 mutation and optic atrophy with bilateral brainstem lesions', Biochimica et Biophysica Acta - Molecular Basis of Disease, vol. 1832, no. 3, pp. 445-452. https://doi.org/10.1016/j.bbadis.2012.12.002

Cybrid studies establish the causal link between the mtDNA m.3890G>A/MT-ND1 mutation and optic atrophy with bilateral brainstem lesions. / Caporali, Leonardo; Ghelli, Anna Maria; Iommarini, Luisa; Maresca, Alessandra; Valentino, Maria Lucia; La Morgia, Chiara; Liguori, Rocco; Zanna, Claudia; Barboni, Piero; De Nardo, Vera; Martinuzzi, Andrea; Rizzo, Giovanni; Tonon, Caterina; Lodi, Raffaele; Calvaruso, Maria Antonietta; Cappelletti, Martina; Porcelli, Anna Maria; Achilli, Alessandro; Pala, Maria; Torroni, Antonio; Carelli, Valerio.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1832, No. 3, 01.03.2013, p. 445-452.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cybrid studies establish the causal link between the mtDNA m.3890G>A/MT-ND1 mutation and optic atrophy with bilateral brainstem lesions

AU - Caporali, Leonardo

AU - Ghelli, Anna Maria

AU - Iommarini, Luisa

AU - Maresca, Alessandra

AU - Valentino, Maria Lucia

AU - La Morgia, Chiara

AU - Liguori, Rocco

AU - Zanna, Claudia

AU - Barboni, Piero

AU - De Nardo, Vera

AU - Martinuzzi, Andrea

AU - Rizzo, Giovanni

AU - Tonon, Caterina

AU - Lodi, Raffaele

AU - Calvaruso, Maria Antonietta

AU - Cappelletti, Martina

AU - Porcelli, Anna Maria

AU - Achilli, Alessandro

AU - Pala, Maria

AU - Torroni, Antonio

AU - Carelli, Valerio

PY - 2013/3/1

Y1 - 2013/3/1

N2 - Complex I (CI) deficiency is a frequent cause of mitochondrial disorders and, in most cases, is due to mutations in CI subunit genes encoded by mitochondrial DNA (mtDNA). In this study, we establish the pathogenic role of the heteroplasmic mtDNA m.3890G>A/. MT- ND1 (p.R195Q) mutation, which affects an extremely conserved amino acid position in ND1 subunit of CI. This mutation was found in a young-adult male with optic atrophy resembling Leber's hereditary optic neuropathy (LHON) and bilateral brainstem lesions. The only previously reported case with this mutation was a girl with fatal infantile Leigh syndrome with bilateral brainstem lesions. Transfer of the mutant mtDNA in the cybrid cell system resulted in a marked reduction of CI activity and CI-dependent ATP synthesis in the presence of a normally assembled enzyme.These findings establish the pathogenicity of the m.3890G>A/. MT- ND1 mutation and remark the link between CI mutations affecting the mtDNA-encoded ND subunits and LHON-like optic atrophy, which may be complicated by bilateral and symmetric lesions affecting the central nervous system. Peculiar to this mutation is the distribution of the brainstem lesions, with sparing of the striatum in both patients.

AB - Complex I (CI) deficiency is a frequent cause of mitochondrial disorders and, in most cases, is due to mutations in CI subunit genes encoded by mitochondrial DNA (mtDNA). In this study, we establish the pathogenic role of the heteroplasmic mtDNA m.3890G>A/. MT- ND1 (p.R195Q) mutation, which affects an extremely conserved amino acid position in ND1 subunit of CI. This mutation was found in a young-adult male with optic atrophy resembling Leber's hereditary optic neuropathy (LHON) and bilateral brainstem lesions. The only previously reported case with this mutation was a girl with fatal infantile Leigh syndrome with bilateral brainstem lesions. Transfer of the mutant mtDNA in the cybrid cell system resulted in a marked reduction of CI activity and CI-dependent ATP synthesis in the presence of a normally assembled enzyme.These findings establish the pathogenicity of the m.3890G>A/. MT- ND1 mutation and remark the link between CI mutations affecting the mtDNA-encoded ND subunits and LHON-like optic atrophy, which may be complicated by bilateral and symmetric lesions affecting the central nervous system. Peculiar to this mutation is the distribution of the brainstem lesions, with sparing of the striatum in both patients.

KW - Complex I

KW - Mitochondrial disorder

KW - MT-ND1

KW - Vision loss

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DO - 10.1016/j.bbadis.2012.12.002

M3 - Article

VL - 1832

SP - 445

EP - 452

JO - Biochimica et Biophysica Acta - Molecular Basis of Disease

T2 - Biochimica et Biophysica Acta - Molecular Basis of Disease

JF - Biochimica et Biophysica Acta - Molecular Basis of Disease

SN - 0925-4439

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