A novel mitochondrial ATPase 6 point 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: 9.98). 09/1995; 38(3):468-72. DOI: 10.1002/ana.410380321
Source: PubMed


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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    • "Interestingly, some correlations have been described between MRI findings and specific genetic defects. In patients with ATPase 6 mutations MRI typically shows necrosis in the putamina, demyelization in the corona radiata and cerebellar and brainstem atrophy in the final stages [28]. Patients with PDHc deficiency usually present with lesions in the basal ganglia, brainstem and dentate nuclei, being the globus pallidus frequently involved [29]. "
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    ABSTRACT: Background The clinical characteristics distinguishing treatable thiamine transporter-2 deficiency (ThTR2) due to SLC19A3 genetic defects from the other devastating causes of Leigh syndrome are sparse. Methods We report the clinical follow-up after thiamine and biotin supplementation in four children with ThTR2 deficiency presenting with Leigh and biotin-thiamine-responsive basal ganglia disease phenotypes. We established whole-blood thiamine reference values in 106 non-neurological affected children and monitored thiamine levels in SLC19A3 patients after the initiation of treatment. We compared our results with those of 69 patients with ThTR2 deficiency after a review of the literature. Results At diagnosis, the patients were aged 1 month to 17 years, and all of them showed signs of acute encephalopathy, generalized dystonia, and brain lesions affecting the dorsal striatum and medial thalami. One patient died of septicemia, while the remaining patients evidenced clinical and radiological improvements shortly after the initiation of thiamine. Upon follow-up, the patients received a combination of thiamine (10–40 mg/kg/day) and biotin (1–2 mg/kg/day) and remained stable with residual dystonia and speech difficulties. After establishing reference values for the different age groups, whole-blood thiamine quantification was a useful method for treatment monitoring. Conclusions ThTR2 deficiency is a reversible cause of acute dystonia and Leigh encephalopathy in the pediatric years. Brain lesions affecting the dorsal striatum and medial thalami may be useful in the differential diagnosis of other causes of Leigh syndrome. Further studies are needed to validate the therapeutic doses of thiamine and how to monitor them in these patients.
    Full-text · Article · Jun 2014 · Orphanet Journal of Rare Diseases
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    • "m.9176T>G/C The clinical picture is characterized by familial bilateral striatal necrosis (FBSN) and Leigh syndrome (Thyagarajan et al. 1995; Dionisi-Vici et al. 1998). A hereditary spastic paraplegia-like disorder has been described in a family carrying the homoplasmic m.9176T>C mutation (Verny et al. 2011). "
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    ABSTRACT: Human mitochondrial (mt) ATP synthase, or complex V consists of two functional domains: F(1), situated in the mitochondrial matrix, and F(o), located in the inner mitochondrial membrane. Complex V uses the energy created by the proton electrochemical gradient to phosphorylate ADP to ATP. This review covers the architecture, function and assembly of complex V. The role of complex V di-and oligomerization and its relation with mitochondrial morphology is discussed. Finally, pathology related to complex V deficiency and current therapeutic strategies are highlighted. Despite the huge progress in this research field over the past decades, questions remain to be answered regarding the structure of subunits, the function of the rotary nanomotor at a molecular level, and the human complex V assembly process. The elucidation of more nuclear genetic defects will guide physio(patho)logical studies, paving the way for future therapeutic interventions.
    Full-text · Article · Aug 2011 · Journal of Inherited Metabolic Disease
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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.
    Full-text · Article · Apr 2009 · Journal of Cellular Biochemistry
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