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

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 mut...

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Autores principales: Alston, Charlotte L., Ceccatelli Berti, Camilla, Blakely, Emma L., Oláhová, Monika, He, Langping, McMahon, Colin J., Olpin, Simon E., Hargreaves, Iain P., Nolli, Cecilia, McFarland, Robert, Goffrini, Paola, O’Sullivan, Maureen J., Taylor, Robert W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4495259/
https://www.ncbi.nlm.nih.gov/pubmed/26008905
http://dx.doi.org/10.1007/s00439-015-1568-z
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author Alston, Charlotte L.
Ceccatelli Berti, Camilla
Blakely, Emma L.
Oláhová, Monika
He, Langping
McMahon, Colin J.
Olpin, Simon E.
Hargreaves, Iain P.
Nolli, Cecilia
McFarland, Robert
Goffrini, Paola
O’Sullivan, Maureen J.
Taylor, Robert W.
author_facet Alston, Charlotte L.
Ceccatelli Berti, Camilla
Blakely, Emma L.
Oláhová, Monika
He, Langping
McMahon, Colin J.
Olpin, Simon E.
Hargreaves, Iain P.
Nolli, Cecilia
McFarland, Robert
Goffrini, Paola
O’Sullivan, Maureen J.
Taylor, Robert W.
author_sort Alston, Charlotte L.
collection PubMed
description 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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spelling pubmed-44952592015-07-09 A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiency Alston, Charlotte L. Ceccatelli Berti, Camilla Blakely, Emma L. Oláhová, Monika He, Langping McMahon, Colin J. Olpin, Simon E. Hargreaves, Iain P. Nolli, Cecilia McFarland, Robert Goffrini, Paola O’Sullivan, Maureen J. Taylor, Robert W. Hum Genet Original Investigation 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. Springer Berlin Heidelberg 2015-05-26 2015 /pmc/articles/PMC4495259/ /pubmed/26008905 http://dx.doi.org/10.1007/s00439-015-1568-z Text en © The Author(s) 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Investigation
Alston, Charlotte L.
Ceccatelli Berti, Camilla
Blakely, Emma L.
Oláhová, Monika
He, Langping
McMahon, Colin J.
Olpin, Simon E.
Hargreaves, Iain P.
Nolli, Cecilia
McFarland, Robert
Goffrini, Paola
O’Sullivan, Maureen J.
Taylor, Robert W.
A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiency
title A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiency
title_full A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiency
title_fullStr A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiency
title_full_unstemmed A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiency
title_short A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiency
title_sort recessive homozygous p.asp92gly sdhd mutation causes prenatal cardiomyopathy and a severe mitochondrial complex ii deficiency
topic Original Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4495259/
https://www.ncbi.nlm.nih.gov/pubmed/26008905
http://dx.doi.org/10.1007/s00439-015-1568-z
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