title: A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiency.
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.
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Alston
authors.forename: Camilla
authors.initials: C
authors.lastname: Ceccatelli Berti
authors.forename: Emma L
authors.initials: EL
authors.lastname: Blakely
authors.forename: Monika
authors.initials: M
authors.lastname: Oláhová
authors.forename: Langping
authors.initials: L
authors.lastname: He
authors.forename: Colin J
authors.initials: CJ
authors.lastname: McMahon
authors.forename: Simon E
authors.initials: SE
authors.lastname: Olpin
authors.forename: Iain P
authors.initials: IP
authors.lastname: Hargreaves
authors.forename: Cecilia
authors.initials: C
authors.lastname: Nolli
authors.forename: Robert
authors.initials: R
authors.lastname: McFarland
authors.forename: Paola
authors.initials: P
authors.lastname: Goffrini
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: O'Sullivan
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
mesh_terms: D019943:Amino Acid Substitution; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000201:enzymology / Q000235:genetics*; D002952:Citric Acid Cycle / Q000235:genetics; D005808:Genes, Recessive; D006330:Heart Defects, Congenital / Q000201:enzymology / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics*; D020125:Mutation, Missense; D013385:Succinate Dehydrogenase / Q000235:genetics*
chemical_list: D024101:Mitochondrial Proteins; C491545:SDHD protein, human; D013385:Succinate Dehydrogenase