Two novel mutations of SURF1 in Leigh syndrome with cytochrome c oxidase deficiency

Teraoka, Michio; Yokoyama, Yuji; Ninomiya, Shinsuke; Inoue, Chiemi; Yamashita, S.; Seino, Yoshiki

doi:10.1007/s004399900191

Cited by 32 publications

(20 citation statements)

References 9 publications

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“…However, approximately a third of our SURF1-deficient muscle specimens (and the remaining two reports of ultrastructural findings in the literature)7 8 did not demonstrate any ultrastructural anomalies of the mitochondria.…”

Section: Discussioncontrasting

confidence: 43%

Light and electron microscopy characteristics of the muscle of patients withSURF1gene mutations associated with Leigh disease

Pronicki

Matyja

Piekutowska‐Abramczuk

et al. 2007

J Clin Pathol

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Aims:Leigh syndrome (LS) is characterised by almost identical brain changes despite considerable causal heterogeneity. SURF1 gene mutations are among the most frequent causes of LS. Although deficiency of cytochrome c oxidase (COX) is a typical feature of the muscle in SURF1-deficient LS, other abnormalities have been rarely described. The aim of the present work is to assess the skeletal muscle morphology coexisting with SURF1 mutations from our own research and in the literature.Methods:Muscle samples from 21 patients who fulfilled the criteria of LS and SURF1 mutations (14 homozygotes and 7 heterozygotes of c.841delCT) were examined by light and electron microscopy.Results:Diffuse decreased activity or total deficit of COX was revealed histochemically in all examined muscles. No ragged red fibres (RRFs) were seen. Lipid accumulation and fibre size variability were found in 14 and 9 specimens, respectively. Ultrastructural assessment showed several mitochondrial abnormalities, lipid deposits, myofibrillar disorganisation and other minor changes. In five cases no ultrastructural changes were found. Apart from slight correlation between lipid accumulation shown by histochemical and ultrastructural techniques, no other correlations were revealed between parameters investigated, especially between severity of morphological changes and the patient’s age at the biopsy.Conclusion:Histological and histochemical features of muscle of genetically homogenous SURF1-deficient LS were reproducible in detection of COX deficit. Minor muscle changes were not commonly present. Also, ultrastructural abnormalities were not a consistent feature. It should be emphasised that SURF1-deficient muscle assessed in the light and electron microscopy panel may be interpreted as normal if COX staining is not employed.

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Section: Discussioncontrasting

confidence: 43%

Light and electron microscopy characteristics of the muscle of patients withSURF1gene mutations associated with Leigh disease

Pronicki

Matyja

Piekutowska‐Abramczuk

et al. 2007

J Clin Pathol

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“…Further studies are necessary to characterize the COX deficiency affecting patients 4, 6, and 7. However, we have confirmed that SURF1 mutations are responsible for Leigh syndrome associated with severe COX deficiency (12) and found a new phenotype of late Leigh syndrome associated with SURF1 mutations never described previously (2,3,8,13). …”

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confidence: 82%

New Splicing-site Mutations in the SURF1Gene in Leigh Syndrome Patients

Péquignot¹,

Desguerre

Dey

et al. 2001

Journal of Biological Chemistry

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The gene SURF1 encodes a factor involved in the biogenesis of cytochrome c oxidase, the last complex in the respiratory chain. Mutations of the SURF1 gene result in Leigh syndrome and severe cytochrome c oxidase deficiency. Analysis of seven unrelated patients with cytochrome c oxidase deficiency and typical Leigh syndrome revealed different SURF1 mutations in four of them. Only these four cases had associated demyelinating neuropathy. Three mutations were novel splicingsite mutations that lead to the excision of exon 6. Two different novel heterozygous mutations were found at the same guanine residue at the donor splice site of intron 6; one was a deletion, whereas the other was a transition [588؉1G>A]. The third novel splicing-site mutation was a homozygous [516 -2_516 -1delAG] in intron 5. One patient only had a homozygous polymorphism in the middle of the intron 8 [835؉25C>T]. Western blot analysis showed that Surf1 protein was absent in all four patients harboring mutations. Our studies confirm that the SURF1 gene is an important nuclear gene involved in the cytochrome c oxidase deficiency. We also show that Surf1 protein is not implicated in the assembly of other respiratory chain complexes or the pyruvate dehydrogenase complex. Leigh syndrome (LS),1 or subacute necrotizing encephalomyelopathy (MIM 256000), is a progressive and often fatal neurological disorder in young children, characterized by bilaterally symmetrical necrotic lesions in the brain stem and basal ganglia (1). A common associated biological feature is hyperlactatemia. It is a genetically heterogeneous disease, caused by defects in the enzymes normally involved in the respiratory chain and in mitochondrial energetic metabolism (e.g. pyruvate dehydrogenase). One of the most common enzymatic defects is the deficiency of cytochrome c oxidase (COX), complex IV of the mitochondrial respiratory chain. Recently, mutations in the nuclear SURF1 gene, which encodes a factor involved in COX biogenesis, have been identified in patients with LS (2, 3). This gene is located on chromosome 9q34, consists of nine exons, and encodes a protein of 300 amino acids. We have studied 58 patients who were thought to have LS based on their clinical features and on magnetic resonance imaging (MRI), which showed lesions on the basal ganglia and the brain stem. 15 of these patients presented cytochrome c oxidase deficiency, seven were typical LS, but only four had a severe COX deficiency (LS cox ). 15 other patients were defective in pyruvate dehydrogenase with mutations in the E1 ␣-PDH and Hs-PDX1 genes, 11 were found to have a complex I deficiency, and four had the clinical features of the maternal inheritance Leigh syndrome with a neuropathy ataxia retinitis pigmentosa mutation in the ATPase6 gene of the mitochondrial DNA. We identified six mutations, including three new splicing-site mutations, in the SURF1 gene in the four patients with typical LS and severe COX deficiency. EXPERIMENTAL PROCEDURESPatients-Patient 1 was the first child of non-consanguineous parents...

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“…We selected three known missense mutations in SURF1 LS patients that result in G 124 E, I 246 T, and Y 274 D substitutions in SURF1 (31,39). Gly124 and Tyr274 are conserved residues in SURF1 orthologs, whereas Ile246 is a conserved hydrophobic residue.…”

Section: Characterization Of Human Surf1 Missense Mutations In the Yementioning

confidence: 99%

Analysis of Leigh Syndrome Mutations in the Yeast SURF1 Homolog Reveals a New Member of the Cytochrome Oxidase Assembly Factor Family

Bestwick

Jeong

Khalimonchuk

et al. 2010

Molecular and Cellular Biology

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Two novel mutations of SURF1 in Leigh syndrome with cytochrome c oxidase deficiency

Cited by 32 publications

References 9 publications

Light and electron microscopy characteristics of the muscle of patients withSURF1gene mutations associated with Leigh disease

Light and electron microscopy characteristics of the muscle of patients withSURF1gene mutations associated with Leigh disease

New Splicing-site Mutations in the SURF1Gene in Leigh Syndrome Patients

Analysis of Leigh Syndrome Mutations in the Yeast SURF1 Homolog Reveals a New Member of the Cytochrome Oxidase Assembly Factor Family

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