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A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiency.

Alston CL, Ceccatelli Berti C, Blakely EL, Oláhová M, He L, McMahon CJ, Olpin SE, Hargreaves IP, Nolli C, McFarland R, Goffrini P, O'Sullivan MJ, Taylor RW - Hum. Genet. (2015)

Bottom Line: Subsequent postmortem examination confirmed hypertrophic cardiomyopathy with left ventricular non-compaction.The affected amino acid has been reported as a Dutch founder mutation p.(Asp92Tyr) in families with hereditary head and neck paraganglioma.This is only the second case of mitochondrial complex II deficiency due to inherited SDHD mutations and highlights the importance of sequencing all SDH genes in patients with biochemical and histochemical evidence of isolated mitochondrial complex II deficiency.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.

ABSTRACT
Succinate dehydrogenase (SDH) is a crucial metabolic enzyme complex that is involved in ATP production, playing roles in both the tricarboxylic cycle and the mitochondrial respiratory chain (complex II). Isolated complex II deficiency is one of the rarest oxidative phosphorylation disorders with mutations described in three structural subunits and one of the assembly factors; just one case is attributed to recessively inherited SDHD mutations. We report the pathological, biochemical, histochemical and molecular genetic investigations of a male neonate who had left ventricular hypertrophy detected on antenatal scan and died on day one of life. Subsequent postmortem examination confirmed hypertrophic cardiomyopathy with left ventricular non-compaction. Biochemical analysis of his skeletal muscle biopsy revealed evidence of a severe isolated complex II deficiency and candidate gene sequencing revealed a novel homozygous c.275A>G, p.(Asp92Gly) SDHD mutation which was shown to be recessively inherited through segregation studies. The affected amino acid has been reported as a Dutch founder mutation p.(Asp92Tyr) in families with hereditary head and neck paraganglioma. By introducing both mutations into Saccharomyces cerevisiae, we were able to confirm that the p.(Asp92Gly) mutation causes a more severe oxidative growth phenotype than the p.(Asp92Tyr) mutant, and provides functional evidence to support the pathogenicity of the patient's SDHD mutation. This is only the second case of mitochondrial complex II deficiency due to inherited SDHD mutations and highlights the importance of sequencing all SDH genes in patients with biochemical and histochemical evidence of isolated mitochondrial complex II deficiency.

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a Oxygen consumption rates. Respiration was measured in cells grown in YNB supplemented with 0.6 % glucose at 28 °C. The values observed for the sdh4 mutant cells are reported as a percentage of the wild-type SDH4 cell respiratory rate, 40.46 ± 1.54 nmol min−1 mg−1. b Complex II activity. PMS/DCPIP reductase and decylubiquinone reductase activities were measured in mitochondria extracted from cells grown exponentially at 28 °C in YNB supplemented with 0.6 % glucose. The values of the sdh4 mutants are expressed as percentage of the activities obtained in the wild-type strain
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Fig5: a Oxygen consumption rates. Respiration was measured in cells grown in YNB supplemented with 0.6 % glucose at 28 °C. The values observed for the sdh4 mutant cells are reported as a percentage of the wild-type SDH4 cell respiratory rate, 40.46 ± 1.54 nmol min−1 mg−1. b Complex II activity. PMS/DCPIP reductase and decylubiquinone reductase activities were measured in mitochondria extracted from cells grown exponentially at 28 °C in YNB supplemented with 0.6 % glucose. The values of the sdh4 mutants are expressed as percentage of the activities obtained in the wild-type strain

Mentions: A clear growth defect was observed for the Δsdh4/sdh4D98G strain in ethanol-containing plates incubated both at 28 and 37 °C (Fig. 4a), with growth similar to that of the sdh4 mutant. Contrariwise, the Δsdh4/sdh4D98Y strain did not exhibit an OXPHOS-deficient phenotype at either temperature tested (Fig. 4b) or in either oxidative carbon source analysed (not shown). To further investigate the OXPHOS defect, oxygen consumption and SDH activity were measured. The oxygen consumption rate of the Δsdh4/sdh4D98G mutant was 55 % less than that of the parental strain Δsdh4/SDH4 (Fig. 5a), likewise, succinate dehydrogenase enzyme activities (PMS/DCPIP reductase and decylubiquinone reductase) were both severely reduced, with levels similar to those of the mutant (Fig. 5b). Consistent with the results obtained from growth experiments the oxygen consumption rate of the Δsdh4/sdh4D98Y mutant was not impaired (Fig. 5a) but both SDH activities (PMS/DCPIP reductase and decylubiquinone reductase) were partially reduced (80 and 75 % residual activity) in Δsdh4/sdh4D98Y mitochondria (Fig. 5b). Together, these data support the pathogenicity of our patient’s novel p.(Asp92Gly) SDHD variant.Fig. 4


A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiency.

Alston CL, Ceccatelli Berti C, Blakely EL, Oláhová M, He L, McMahon CJ, Olpin SE, Hargreaves IP, Nolli C, McFarland R, Goffrini P, O'Sullivan MJ, Taylor RW - Hum. Genet. (2015)

a Oxygen consumption rates. Respiration was measured in cells grown in YNB supplemented with 0.6 % glucose at 28 °C. The values observed for the sdh4 mutant cells are reported as a percentage of the wild-type SDH4 cell respiratory rate, 40.46 ± 1.54 nmol min−1 mg−1. b Complex II activity. PMS/DCPIP reductase and decylubiquinone reductase activities were measured in mitochondria extracted from cells grown exponentially at 28 °C in YNB supplemented with 0.6 % glucose. The values of the sdh4 mutants are expressed as percentage of the activities obtained in the wild-type strain
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4495259&req=5

Fig5: a Oxygen consumption rates. Respiration was measured in cells grown in YNB supplemented with 0.6 % glucose at 28 °C. The values observed for the sdh4 mutant cells are reported as a percentage of the wild-type SDH4 cell respiratory rate, 40.46 ± 1.54 nmol min−1 mg−1. b Complex II activity. PMS/DCPIP reductase and decylubiquinone reductase activities were measured in mitochondria extracted from cells grown exponentially at 28 °C in YNB supplemented with 0.6 % glucose. The values of the sdh4 mutants are expressed as percentage of the activities obtained in the wild-type strain
Mentions: A clear growth defect was observed for the Δsdh4/sdh4D98G strain in ethanol-containing plates incubated both at 28 and 37 °C (Fig. 4a), with growth similar to that of the sdh4 mutant. Contrariwise, the Δsdh4/sdh4D98Y strain did not exhibit an OXPHOS-deficient phenotype at either temperature tested (Fig. 4b) or in either oxidative carbon source analysed (not shown). To further investigate the OXPHOS defect, oxygen consumption and SDH activity were measured. The oxygen consumption rate of the Δsdh4/sdh4D98G mutant was 55 % less than that of the parental strain Δsdh4/SDH4 (Fig. 5a), likewise, succinate dehydrogenase enzyme activities (PMS/DCPIP reductase and decylubiquinone reductase) were both severely reduced, with levels similar to those of the mutant (Fig. 5b). Consistent with the results obtained from growth experiments the oxygen consumption rate of the Δsdh4/sdh4D98Y mutant was not impaired (Fig. 5a) but both SDH activities (PMS/DCPIP reductase and decylubiquinone reductase) were partially reduced (80 and 75 % residual activity) in Δsdh4/sdh4D98Y mitochondria (Fig. 5b). Together, these data support the pathogenicity of our patient’s novel p.(Asp92Gly) SDHD variant.Fig. 4

Bottom Line: Subsequent postmortem examination confirmed hypertrophic cardiomyopathy with left ventricular non-compaction.The affected amino acid has been reported as a Dutch founder mutation p.(Asp92Tyr) in families with hereditary head and neck paraganglioma.This is only the second case of mitochondrial complex II deficiency due to inherited SDHD mutations and highlights the importance of sequencing all SDH genes in patients with biochemical and histochemical evidence of isolated mitochondrial complex II deficiency.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.

ABSTRACT
Succinate dehydrogenase (SDH) is a crucial metabolic enzyme complex that is involved in ATP production, playing roles in both the tricarboxylic cycle and the mitochondrial respiratory chain (complex II). Isolated complex II deficiency is one of the rarest oxidative phosphorylation disorders with mutations described in three structural subunits and one of the assembly factors; just one case is attributed to recessively inherited SDHD mutations. We report the pathological, biochemical, histochemical and molecular genetic investigations of a male neonate who had left ventricular hypertrophy detected on antenatal scan and died on day one of life. Subsequent postmortem examination confirmed hypertrophic cardiomyopathy with left ventricular non-compaction. Biochemical analysis of his skeletal muscle biopsy revealed evidence of a severe isolated complex II deficiency and candidate gene sequencing revealed a novel homozygous c.275A>G, p.(Asp92Gly) SDHD mutation which was shown to be recessively inherited through segregation studies. The affected amino acid has been reported as a Dutch founder mutation p.(Asp92Tyr) in families with hereditary head and neck paraganglioma. By introducing both mutations into Saccharomyces cerevisiae, we were able to confirm that the p.(Asp92Gly) mutation causes a more severe oxidative growth phenotype than the p.(Asp92Tyr) mutant, and provides functional evidence to support the pathogenicity of the patient's SDHD mutation. This is only the second case of mitochondrial complex II deficiency due to inherited SDHD mutations and highlights the importance of sequencing all SDH genes in patients with biochemical and histochemical evidence of isolated mitochondrial complex II deficiency.

Show MeSH
Related in: MedlinePlus