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Defective complex I assembly due to C20orf7 mutations as a new cause of Leigh syndrome.

Gerards M, Sluiter W, van den Bosch BJ, de Wit LE, Calis CM, Frentzen M, Akbari H, Schoonderwoerd K, Scholte HR, Jongbloed RJ, Hendrickx AT, de Coo IF, Smeets HJ - J. Med. Genet. (2009)

Bottom Line: Parents were heterozygous and unaffected sibs heterozygous or homozygous wild type.The mutation affects the predicted S-adenosylmethionine (SAM) dependent methyltransferase domain of C20orf7, possibly involved in methylation of NDUFB3 during the assembly process.Blue native gel electrophoresis showed an altered complex I assembly with only 30-40% of mature complex I present in patients and 70-90% in carriers.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Cell Biology, Unit Clinical Genomics, Maastricht University, Maastricht, The Netherlands.

ABSTRACT

Background: Leigh syndrome is an early onset, progressive, neurodegenerative disorder with developmental and motor skills regression. Characteristic magnetic resonance imaging abnormalities consist of focal bilateral lesions in the basal ganglia and/or the brainstem. The main cause is a deficiency in oxidative phosphorylation due to mutations in an mtDNA or nuclear oxidative phosphorylation gene.

Methods and results: A consanguineous Moroccan family with Leigh syndrome comprise 11 children, three of which are affected. Marker analysis revealed a homozygous region of 11.5 Mb on chromosome 20, containing 111 genes. Eight possible mitochondrial candidate genes were sequenced. Patients were homozygous for an unclassified variant (p.P193L) in the cardiolipin synthase gene (CRLS1). As this variant was present in 20% of a Moroccan control population and enzyme activity was only reduced to 50%, this could not explain the rare clinical phenotype in our family. Patients were also homozygous for an amino acid substitution (p.L159F) in C20orf7, a new complex I assembly factor. Parents were heterozygous and unaffected sibs heterozygous or homozygous wild type. The mutation affects the predicted S-adenosylmethionine (SAM) dependent methyltransferase domain of C20orf7, possibly involved in methylation of NDUFB3 during the assembly process. Blue native gel electrophoresis showed an altered complex I assembly with only 30-40% of mature complex I present in patients and 70-90% in carriers.

Conclusions: A new cause of Leigh syndrome can be a defect in early complex I assembly due to C20orf7 mutations.

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Related in: MedlinePlus

Mutation analysis in the C20orf7 gene reveals a c.477A→C mutation changing leucine at position 159 to phenylalanine. (A) Sequence analysis of exon 5 of the C20orf7 gene. (B) Conservation of leucine 159 from man to Drosophila (ClustalW).
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fig3: Mutation analysis in the C20orf7 gene reveals a c.477A→C mutation changing leucine at position 159 to phenylalanine. (A) Sequence analysis of exon 5 of the C20orf7 gene. (B) Conservation of leucine 159 from man to Drosophila (ClustalW).

Mentions: A second homozygous mutation was identified in the C20orf7 gene. Both patients (IV7 and IV11) were homozygous for an A-to-C transversion at nucleotide 477 in exon 5 of isoform 1 (NM_024120.3), whereas both parents and two other sibs were heterozygous and one sib was wild type (figures 1 and 3a). Two isoforms of C20orf7 are currently known, consisting of, respectively, 345 amino acids (isoform 1 (NM_024120.3), containing exons 1–11), and 317 amino acids (isoform 2 (NM_001039375.1), containing exons 1–4 and 6–11). The mutation is present in isoform 1 only. The mutation changed a leucine at position 159 to phenylalanine in the highly conserved (from man to Drosophila) S-adenosylmethionine (SAM) dependent methyltransferase domain of the protein (figure 3b). Analysis with the program SOPM41 shows that the secondary structure is likely to change due to breakage of an α helix in the mutant protein (data not shown). SOPM uses sequence information and similarities to predict secondary protein structures. The mutation was not present in 110 Moroccan and 312 Dutch alleles, supporting a pathogenic role for the mutation.


Defective complex I assembly due to C20orf7 mutations as a new cause of Leigh syndrome.

Gerards M, Sluiter W, van den Bosch BJ, de Wit LE, Calis CM, Frentzen M, Akbari H, Schoonderwoerd K, Scholte HR, Jongbloed RJ, Hendrickx AT, de Coo IF, Smeets HJ - J. Med. Genet. (2009)

Mutation analysis in the C20orf7 gene reveals a c.477A→C mutation changing leucine at position 159 to phenylalanine. (A) Sequence analysis of exon 5 of the C20orf7 gene. (B) Conservation of leucine 159 from man to Drosophila (ClustalW).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2921275&req=5

fig3: Mutation analysis in the C20orf7 gene reveals a c.477A→C mutation changing leucine at position 159 to phenylalanine. (A) Sequence analysis of exon 5 of the C20orf7 gene. (B) Conservation of leucine 159 from man to Drosophila (ClustalW).
Mentions: A second homozygous mutation was identified in the C20orf7 gene. Both patients (IV7 and IV11) were homozygous for an A-to-C transversion at nucleotide 477 in exon 5 of isoform 1 (NM_024120.3), whereas both parents and two other sibs were heterozygous and one sib was wild type (figures 1 and 3a). Two isoforms of C20orf7 are currently known, consisting of, respectively, 345 amino acids (isoform 1 (NM_024120.3), containing exons 1–11), and 317 amino acids (isoform 2 (NM_001039375.1), containing exons 1–4 and 6–11). The mutation is present in isoform 1 only. The mutation changed a leucine at position 159 to phenylalanine in the highly conserved (from man to Drosophila) S-adenosylmethionine (SAM) dependent methyltransferase domain of the protein (figure 3b). Analysis with the program SOPM41 shows that the secondary structure is likely to change due to breakage of an α helix in the mutant protein (data not shown). SOPM uses sequence information and similarities to predict secondary protein structures. The mutation was not present in 110 Moroccan and 312 Dutch alleles, supporting a pathogenic role for the mutation.

Bottom Line: Parents were heterozygous and unaffected sibs heterozygous or homozygous wild type.The mutation affects the predicted S-adenosylmethionine (SAM) dependent methyltransferase domain of C20orf7, possibly involved in methylation of NDUFB3 during the assembly process.Blue native gel electrophoresis showed an altered complex I assembly with only 30-40% of mature complex I present in patients and 70-90% in carriers.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Cell Biology, Unit Clinical Genomics, Maastricht University, Maastricht, The Netherlands.

ABSTRACT

Background: Leigh syndrome is an early onset, progressive, neurodegenerative disorder with developmental and motor skills regression. Characteristic magnetic resonance imaging abnormalities consist of focal bilateral lesions in the basal ganglia and/or the brainstem. The main cause is a deficiency in oxidative phosphorylation due to mutations in an mtDNA or nuclear oxidative phosphorylation gene.

Methods and results: A consanguineous Moroccan family with Leigh syndrome comprise 11 children, three of which are affected. Marker analysis revealed a homozygous region of 11.5 Mb on chromosome 20, containing 111 genes. Eight possible mitochondrial candidate genes were sequenced. Patients were homozygous for an unclassified variant (p.P193L) in the cardiolipin synthase gene (CRLS1). As this variant was present in 20% of a Moroccan control population and enzyme activity was only reduced to 50%, this could not explain the rare clinical phenotype in our family. Patients were also homozygous for an amino acid substitution (p.L159F) in C20orf7, a new complex I assembly factor. Parents were heterozygous and unaffected sibs heterozygous or homozygous wild type. The mutation affects the predicted S-adenosylmethionine (SAM) dependent methyltransferase domain of C20orf7, possibly involved in methylation of NDUFB3 during the assembly process. Blue native gel electrophoresis showed an altered complex I assembly with only 30-40% of mature complex I present in patients and 70-90% in carriers.

Conclusions: A new cause of Leigh syndrome can be a defect in early complex I assembly due to C20orf7 mutations.

Show MeSH
Related in: MedlinePlus