A SURF1 gene mutation presenting as isolated leukodystrophy

Rahman, Shamina; Brown, Ruth; Chong, W.K.; Wilson, Callum; Brown, Garry K.

doi:10.1002/ana.1060

Cited by 70 publications

(39 citation statements)

References 13 publications

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“…Two patients have been described with complex III defects, one had a mutation in cytochrome b subunit of complex III and the other was without a recognized mutation but a defect in enzyme activity (Majoie et al, 2002;Seijo-Martinez et al, 2003). At least 5 patients with defects in complex IV have demonstrated white matter changes (Zafeiriou et al, 1995;Rahman et al, 2001;Jaksch et al, 2001). One patient with multiple ETC defects with leukodystrophy has been reported (Moroni et al, 2002).…”

Section: Isolated Electron Transport Chain Disordersmentioning

confidence: 99%

Neuroimaging of mitochondrial disease

2008

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Section: Isolated Electron Transport Chain Disordersmentioning

confidence: 99%

Neuroimaging of mitochondrial disease

2008

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“…20,21 All patients with SURF1-associated LS show severely reduced COX activity in muscle and fibroblasts (5%-21% of normal values). 8,13,[22][23][24][25] In SURF1 null human samples, residual amounts of fully assembled, functionally active complex IV were found, suggesting partial functional redundancy.…”

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SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease

et al. 2013

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Objective: To investigate whether mutations in the SURF1 gene are a cause of Charcot-MarieTooth (CMT) disease. Methods:We describe 2 patients from a consanguineous family with demyelinating autosomal recessive CMT disease (CMT4) associated with the homozygous splice site mutation c.107-2A.G in the SURF1 gene, encoding an assembly factor of the mitochondrial respiratory chain complex IV. This observation led us to hypothesize that mutations in SURF1 might be an unrecognized cause of CMT4, and we investigated SURF1 in a total of 40 unrelated patients with CMT4 after exclusion of mutations in known CMT4 genes. The functional impact of c.107-2A.G on splicing, amount of SURF1 protein, and on complex IV activity and assembly was analyzed.Results: Another patient with CMT4 was found to harbor 2 additional SURF1 mutations. All 3 patients with SURF1-associated CMT4 presented with severe childhood-onset neuropathy, motor nerve conduction velocities ,25 m/s, and lactic acidosis. Two patients had brain MRI abnormalities, including putaminal and periaqueductal lesions, and developed cerebellar ataxia years after polyneuropathy. The c.107-2A.G mutation produced no normally spliced transcript, leading to SURF1 absence. However, complex IV remained partially functional in muscle and fibroblasts. Conclusions:We found SURF1 mutations in 5% of families (2/41) presenting with CMT4. SURF1 should be systematically screened in patients with childhood-onset severe demyelinating neuropathy and additional features such as lactic acidosis, brain MRI abnormalities, and cerebellar ataxia developing years after polyneuropathy. Peripheral neuropathies are a well-known complication of mitochondrial DNA and nuclearencoded mitochondrial gene mutations. For instance, patients with mutations in the nuclearencoded mitochondrial genes MFN2 and GDAP1, which encode outer mitochondrial membrane proteins, usually present with axonal and demyelinating forms of Charcot-Marie-Tooth (CMT) disease, respectively.1 Moreover, patients with mutations in the mitochondrial DNA gene MTATP6, which encodes the ATP6 subunit of the mitochondrial respiratory chain (MRC) complex V, may present with axonal CMT (CMT2). 2The determination of the genetic cause is a major challenge in rare neuromuscular diseases such as autosomal recessive demyelinating CMT (CMT4). We investigated a consanguineous family in which 2 patients with CMT4 harbored a homozygous splice site mutation in SURF1, encoding an assembly factor of the MRC complex IV (cytochrome c oxidase [COX]). Despite this defect, we detected some residual assembly and function of COX in fibroblasts and muscle of both patients. We then screened for SURF1 mutations in a cohort of 40 unrelated patients

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“…The activity of this enzyme is reduced in neurodegenerative diseases, such as Alzheimer disease (3,4). Among respiratory chain deficiencies presented in infancy and early childhood in humans, cytochrome c oxidase (COX) 2 deficiency is the most commonly diagnosed (5). COX deficiency is found with different clinical phenotypes primarily affecting organs with high energy demand, such as the brain, skeletal muscle, heart, and kidney (6).…”

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Nuclear Respiratory Factor 1 Regulates All Ten Nuclear-encoded Subunits of Cytochrome c Oxidase in Neurons

Dhar

Ongwijitwat

Wong‐Riley

2008

Journal of Biological Chemistry

146

188

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Cytochrome c oxidase (COX) is one of only four bigenomic proteins in mammalian cells, having ten subunits encoded in the nuclear genome and three in the mitochondrial DNA. The mechanism of its bigenomic control is not well understood. The ten nuclear subunits are on different chromosomes, and the possibility of their coordinate regulation by the same transcription factor(s) deserves serious consideration. The present study tested our hypothesis that nuclear respiratory factor 1 (NRF-1) serves such a role in subunit coordination. Following in silico analysis of murine nuclear-encoded COX subunit promoters, electrophoretic mobility shift and supershift assays indicated NRF-1 binding to all ten promoters. In vivo chromatin immunoprecipitation assays also showed NRF-1 binding to all ten promoters in murine neuroblastoma cells. Site-directed mutagenesis of putative NRF-1 binding sites confirmed the functionality of NRF-1 binding on all ten COX promoters. These sites are highly conserved among mice, rats, and humans. Silencing of NRF-1 with RNA interference reduced all ten COX subunit mRNAs and mRNAs of other genes involved in mitochondrial biogenesis. We conclude that NRF-1 plays a significant role in coordinating the transcriptional regulation of all ten nuclearencoded COX subunits in neurons. Moreover, NRF-1 is known to activate mitochondrial transcription factors A and B, thereby indirectly regulating the expressions of the three mitochondrial-encoded COX subunits. Thus, NRF-1 and our previously described NRF-2 prove to be the two key bigenomic coordinators for transcriptional regulation of all cytochrome c oxidase subunits in neurons. Possible interactions between the NRFs will be investigated in the future.Cytochrome c oxidase or complex IV is a large transmembrane protein located in the inner mitochondrial membrane of eukaryotes and plasma membrane of prokaryotes. It is the terminal enzyme of the electron transport chain, catalyzing the transfer of electrons from reduced cytochrome c to molecular oxygen to form water. The important outcome of this reaction is the generation of ATP through the coupled process of oxidative phosphorylation. Neurons are highly dependent upon ATP for their activity and functions (1). Approximately 90% of ATP generated in the brain is synthesized in the mitochondria via oxidative phosphorylation (2). The activity of this enzyme is reduced in neurodegenerative diseases, such as Alzheimer disease (3, 4). Among respiratory chain deficiencies presented in infancy and early childhood in humans, cytochrome c oxidase (COX) 2 deficiency is the most commonly diagnosed (5). COX deficiency is found with different clinical phenotypes primarily affecting organs with high energy demand, such as the brain, skeletal muscle, heart, and kidney (6).COX is a complex of 13 different subunits, 3 of which (I, II, and III) are encoded in the mitochondrial DNA, and the remaining 10 are nuclear-encoded (7). To form a functional holoenzyme with 1:1 stoichiometry, exact coordination is essential between the two...

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A SURF1 gene mutation presenting as isolated leukodystrophy

Cited by 70 publications

References 13 publications

Neuroimaging of mitochondrial disease

Neuroimaging of mitochondrial disease

SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease

Nuclear Respiratory Factor 1 Regulates All Ten Nuclear-encoded Subunits of Cytochrome c Oxidase in Neurons

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