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Case Reports
. 2015 Aug;134(8):869-79.
doi: 10.1007/s00439-015-1568-z. Epub 2015 May 26.

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

Charlotte L Alston  1 , Camilla Ceccatelli Berti, Emma L Blakely, Monika Oláhová, Langping He, Colin J McMahon, Simon E Olpin, Iain P Hargreaves, Cecilia Nolli, Robert McFarland, Paola Goffrini, Maureen J O'Sullivan, Robert W Taylor
Affiliations
Case Reports

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

Charlotte L Alston et al. Hum Genet. 2015 Aug.

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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Figures

Fig. 1
Fig. 1
Macroscopic and microscopic analysis of patient cardiac and skeletal muscle. a Macroscopic examination of patient heart revealed obvious non-compaction of the hypertrophic left ventricle. b Microscopic assessment of left ventricle confirms non-compaction compared to neonatal control tissue (c). Histochemical assessment of patient muscle biopsy shows a marked decrease in the activity of succinate dehydrogenase activity (d) compared with a control muscle (e)
Fig. 2
Fig. 2
Molecular genetic and in silico investigations. a Identification of a pathogenic SDHD mutation. A homozygous c.275A>G, p.(Asp92Gly) SDHD mutation was identified in the proband, with parental DNA screening supporting recessive inheritance. The mutation affects a highly conserved p.Asp92 residue in the SDHD-encoded subunit of succinate dehydrogenase (SDH). b Structural modelling. I-TASSER prediction of control and patient SDHD tertiary structure shows the p.Asp92 residue located within a transmembrane helix domain and the p.Asp92Gly substitution is predicted to have little impact on SDHD tertiary structure. c PSIPRED output predicts minor alterations to two of the SDHD helices from the patient p.(Asp92Gly) and HNPGL p.(Asp92Tyr) substitutions compared to control sequence. Predicted helix residues shown in pink; unshaded residues are located in coil domains. d Multiple sequence alignment of this region of the SDHD subunit was performed using ClustalW and confirms that the p.(Asp92Gly) mutation affects an evolutionary conserved residue (shaded). Alignments were manually corrected on the basis of the pairwise alignment obtained with PSI-BLAST
Fig. 3
Fig. 3
Investigation of OXPHOS complex activities and protein expression in patient and controls. a BN-PAGE analysis of mitochondria isolated from patient and control muscle homogenates revealed a reduction of assembled complex II in patient muscle with normal assembly of all other OXPHOS complexes. b SDS-PAGE analysis of patient and control proteins probed with antibodies against Porin (a loading control) and the SDHA and SDHD subunits of succinate dehydrogenase revealed a stark reduction in SDH steady-state protein levels in patient muscle, consistent with subunit degradation thereby supporting the pathogenicity of the p.(Asp92Gly) variant
Fig. 4
Fig. 4
Oxidative growth phenotype in yeast. The strain BY4741 ∆sdh4 was transformed with a pFL38 plasmid carrying either the wild-type SDH4, the empty vector or the mutant alleles sdh4 D98G and sdh4 D98Y. Equal amounts of serially diluted cells from exponentially grown cultures (105, 104, 103, 102, 101) were spotted onto yeast nitrogen base (YNB) plates supplemented with either 2 % glucose or 2 % ethanol. The growth was scored after 3-day incubation at 28 °C (a) and 37 °C (b)
Fig. 5
Fig. 5
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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