A novel mitochondrial ATPase 6 mutation in familial bilateral striatal necrosis

H. Houston Merritt Clinical Research Center for Muscular Dystrophy and Related Disease, Columbia-Presbyterian Hospital Medical Center, New York, NY, USA.
Annals of Neurology (Impact Factor: 11.91). 09/1995; 38(3):468-72. DOI: 10.1002/ana.410380321
Source: PubMed

ABSTRACT A T-to-C transition at nucleotide (nt) 9176 in the mitochondrial adenosine triphosphatase 6 (ATPase 6) gene was detected in 2 brothers with a neurological disorder resembling Leigh syndrome. The mutation was also present in the 2 other siblings and in the mother, who were asymptomatic. In the more severely affected boy (the proband), the mutation was homoplasmic in muscle, leucocytes, and fibroblasts. In leucocytes from his affected brother, 98% of mtDNA was mutant. Heteroplasmy of varying degrees was seen in leucocytes from the mother and the 2 unaffected siblings. The mutation changes a highly conserved leucine residue near the carboxyl terminus of the mitochondrial ATPase 6 subunit to proline. It could not be detected in 168 control subjects. Studies of ATP synthesis and hydrolysis in fibroblasts from the proband were normal.

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Available from: Dominic Thyagarajan, Apr 09, 2014
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    • "The pathogenic consequences of the NARP/MILS associated mutations in the ATPase6 gene—L156R, L217R, L156P, and L217P—have been studied largely in primary cells [Tatuch and Robinson, 1993; Thyagarajan et al., 1995; Vazquez-Memije et al., 1998; Carrozzo et al., 2001] and transmitochondrial cybrids [Trounce et al., 1994; Manfredi et al., 1999] but never simultaneously to pinpoint specific differences which might be relevant to the severity of the associated phenotypes. To expand our understanding of the pathogenesis, and disclose possible similarities or differences, we evaluated for the first time together the effects of the L156R, L217R, L156P, and L217P mutations in primary cells and in cybrid clones, across biochemical and cellular studies. "
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    ABSTRACT: The smallest rotary motor of living cells, F0F1-ATP synthase, couples proton flow-generated by the OXPHOS system-from the intermembrane space back to the matrix with the conversion of ADP to ATP. While all mutations affecting the multisubunit complexes of the OXPHOS system probably impact on the cell's output of ATP, only mutations in complex V can be considered to affect this output directly. So far, most of the F0F1-ATP synthase variations have been detected in the mitochondrial ATPase6 gene. In this study, the four most frequent mutations in the ATPase6 gene, namely L156R, L217R, L156P, and L217P, are studied for the first time together, both in primary cells and in cybrid clones. Arginine ("R") mutations were associated with a much more severe phenotype than Proline ("P") mutations, in terms of both biochemical activity and growth capacity. Also, a threshold effect in both "R" mutations appeared at 50% mutation load. Different mechanisms seemed to emerge for the two "R" mutations: the F1 seemed loosely bound to the membrane in the L156R mutant, whereas the L217R mutant induced low activity of complex V, possibly the result of a reduced rate of proton flow through the A6 channel.
    Journal of Cellular Biochemistry 04/2009; 106(5):878-86. DOI:10.1002/jcb.22055 · 3.37 Impact Factor
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    • "MILS is the maternally inherited form [69] of the Leigh syndrome (LS), a fatal encephalopathy of infancy [70], that has been associated with mutations in nuclear-encoded subunits of complex I and IV [71] [72] [73], as well as pyruvate dehydrogenase [74]. A similar, but less progressive syndrome is the 'Familial Bilateral Striatal Necrosis' (FBSN) [75] "
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    ABSTRACT: In mammals, the majority of cellular ATP is produced by the mitochondrial F1F(O)-ATP synthase through an elaborate catalytic mechanism. While most subunits of this enzymatic complex are encoded by the nuclear genome, a few essential components are encoded in the mitochondrial genome. The biogenesis of this multi-subunit enzyme is a sophisticated multi-step process that is regulated on levels of transcription, translation and assembly. Defects that result in diminished abundance or functional impairment of the F1F(O)-ATP synthase can cause a variety of severe neuromuscular disorders. Underlying mutations have been identified in both the nuclear and the mitochondrial DNA. The pathogenic mechanisms are only partially understood. Currently, the therapeutic options are extremely limited. Alternative methods of treatment have however been proposed, but still encounter several technical difficulties. The application of novel scientific approaches promises to deepen our understanding of the molecular mechanisms of the ATP synthase, unravel novel therapeutic pathways and improve the unfortunate situation of the patients suffering from such diseases.
    Biochimica et Biophysica Acta 07/2008; 1793(1):186-99. DOI:10.1016/j.bbamcr.2008.06.012 · 4.66 Impact Factor
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    • "Other mutations in ATPase 6 gene, e.g. T9176G (L217P), T9185C (L220P) and T9191C (L222P) have also been described in association with LS and familial bilateral striatal necrosis (FBSN) (Thyagarajan et al., 1995; Wilson et al., 2000; Moslemi et al., 2005) (Dionisi-Vici et al., 1998; Carrozzo et al., 2000). "
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    ABSTRACT: Mitochondrial OXPHOS disorders are caused by mutations in mitochondrial or nuclear genes, which directly or indirectly affect mitochondrial oxidative phosphorylation (OXPHOS). Primary mtDNA abnormalities in children are due to rearrangements (deletions or duplications) and point mutations or insertions. Mutations in the nuclear-encoded polypeptide subunits of OXPHOS result in complex I and II deficiency, whereas mutations in the nuclear proteins involved in the assembly of OXPHOS subunits cause defects in complexes I, III, IV, and V. Here, we review recent progress in the identification of mitochondrial and nuclear gene defects and the associated clinical manifestations of these disorders in childhood.
    Mitochondrion 08/2007; 7(4):241-52. DOI:10.1016/j.mito.2007.02.002 · 3.52 Impact Factor
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