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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

Computed tomography (CT) and magnetic resonance imaging (MRI) of patients IV7 and IV11. respectively. (A) CT scan of patients IV7 brain at the age of 5 years. The CT scan shows a hypodensity and slight atrophy of the caudate nuclei and the putamen (arrows) and a widening of the frontal horns of the cerebral ventricles. (B-1) Cranial MRI of patient IV11 at the age of 23 years. Prolongation of T2 weighted signals in the residual part of the nucleus caudatus and putamen and (B-2) at the level of the midbrain of the substantia nigra (arrow).
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fig2: Computed tomography (CT) and magnetic resonance imaging (MRI) of patients IV7 and IV11. respectively. (A) CT scan of patients IV7 brain at the age of 5 years. The CT scan shows a hypodensity and slight atrophy of the caudate nuclei and the putamen (arrows) and a widening of the frontal horns of the cerebral ventricles. (B-1) Cranial MRI of patient IV11 at the age of 23 years. Prolongation of T2 weighted signals in the residual part of the nucleus caudatus and putamen and (B-2) at the level of the midbrain of the substantia nigra (arrow).

Mentions: In a consanguineous family from Morocco with 11 children, three boys presented with Leigh syndrome (figure 1), two of whom were clinically investigated. The third affected sib succumbed for unknown reason at the age of 36 years in Morocco. The disease course is comparable in the two living patients (age 29 and 23 years). At the age of 3 they presented with a progressive spasticity with involvement of arms and legs. At the age of 5 they developed a diminished facial expression. Computed tomography (CT) scanning of the brain of patient IV7 at the age of 5 years showed hypodensity and slight atrophy of the caudate nuclei and the putamen (figure 2a). There is a widening of the frontal horns of the cerebral ventricles. One year later an extrapyramidal movement disorder with dystonic posturing of the right foot was noted. In the years following, the dystonia evolved in a more choreadystonic movement disorder. A delay in mental development became apparent. The dystonia hampered swallowing, necessitating nasal tube feeding. No signs of sensory nerve conduction loss were observed. At the age of 18 years both patients were moderately retarded with an IQ of about 50, had a remarkable good temper, and were severely handicapped by the dysarthria, the dystonic posturing, and the spastic tetraplegia. Their length was just below the third centile, but this was not different from the unaffected sibs and parents.


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)

Computed tomography (CT) and magnetic resonance imaging (MRI) of patients IV7 and IV11. respectively. (A) CT scan of patients IV7 brain at the age of 5 years. The CT scan shows a hypodensity and slight atrophy of the caudate nuclei and the putamen (arrows) and a widening of the frontal horns of the cerebral ventricles. (B-1) Cranial MRI of patient IV11 at the age of 23 years. Prolongation of T2 weighted signals in the residual part of the nucleus caudatus and putamen and (B-2) at the level of the midbrain of the substantia nigra (arrow).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: Computed tomography (CT) and magnetic resonance imaging (MRI) of patients IV7 and IV11. respectively. (A) CT scan of patients IV7 brain at the age of 5 years. The CT scan shows a hypodensity and slight atrophy of the caudate nuclei and the putamen (arrows) and a widening of the frontal horns of the cerebral ventricles. (B-1) Cranial MRI of patient IV11 at the age of 23 years. Prolongation of T2 weighted signals in the residual part of the nucleus caudatus and putamen and (B-2) at the level of the midbrain of the substantia nigra (arrow).
Mentions: In a consanguineous family from Morocco with 11 children, three boys presented with Leigh syndrome (figure 1), two of whom were clinically investigated. The third affected sib succumbed for unknown reason at the age of 36 years in Morocco. The disease course is comparable in the two living patients (age 29 and 23 years). At the age of 3 they presented with a progressive spasticity with involvement of arms and legs. At the age of 5 they developed a diminished facial expression. Computed tomography (CT) scanning of the brain of patient IV7 at the age of 5 years showed hypodensity and slight atrophy of the caudate nuclei and the putamen (figure 2a). There is a widening of the frontal horns of the cerebral ventricles. One year later an extrapyramidal movement disorder with dystonic posturing of the right foot was noted. In the years following, the dystonia evolved in a more choreadystonic movement disorder. A delay in mental development became apparent. The dystonia hampered swallowing, necessitating nasal tube feeding. No signs of sensory nerve conduction loss were observed. At the age of 18 years both patients were moderately retarded with an IQ of about 50, had a remarkable good temper, and were severely handicapped by the dysarthria, the dystonic posturing, and the spastic tetraplegia. Their length was just below the third centile, but this was not different from the unaffected sibs and parents.

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