A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiencyby Charlotte L. Alston, 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

Hum Genet


Genetics (clinical) / Genetics


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Hum Genet

DOI 10.1007/s00439-015-1568-z


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

Charlotte L. Alston1 · Camilla Ceccatelli Berti2 · Emma L. Blakely1 · Monika Oláhová1 ·

Langping He1 · Colin J. McMahon3 · Simon E. Olpin4 · Iain P. Hargreaves5 · Cecilia Nolli2 ·

Robert McFarland1 · Paola Goffrini2 · Maureen J. O’Sullivan6 · Robert W. Taylor1

Received: 20 February 2015 / Accepted: 16 May 2015 © The Author(s) 2015. This article is published with open access at Springerlink.com 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.


Mitochondrial respiratory chain disease arises from defective oxidative phosphorylation (OXPHOS) and represents a common cause of metabolic disease with an estimated prevalence of 1:4300 (Gorman et al. 2015; Skladal et al. 2003). Under aerobic conditions, metabolised glucose, fatty acids and ketones are the OXPHOS substrates, shuttling electrons along the respiratory chain whilst concomitantly creating a proton gradient by actively transporting protons across the mitochondrial membrane. The resultant proton gradient is exploited by ATP synthase to drive ATP production. Under anaerobic conditions, for example where atmospheric oxygen is scarce or during periods of exertion, ATP synthesis is produced primarily during glycolysis (Horscroft and Murray 2014).

The mitoproteome consists of an estimated 1400 proteins (Pagliarini et al. 2008), including the 13 polypeptides and 24 non-coding tRNA and rRNA genes encoded by the

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 * Robert W. Taylor robert.taylor@ncl.ac.uk 1

Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University,

Newcastle upon Tyne NE2 4HH, UK 2

Department of Life Sciences, University of Parma, Parma,

Italy 3

Children’s Heart Centre, Our Lady’s Children’s Hospital,

Crumlin, Dublin, Ireland 4

Department of Clinical Chemistry, Sheffield Children’s

Hospital, Sheffield, UK 5

Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK 6

Department of Pathology, Our Lady’s Children’s Hospital,

Crumlin, Dublin, Ireland

Hum Genet 1 3 mitochondria’s own genetic material (mtDNA) that are exclusively maternally transmitted. The remaining genes of the mitoproteome are located on either the autosomes or sex chromosomes and as such are transmitted from parent to child in a Mendelian fashion. Defects in a number of mtDNA and nuclear-encoded genes have been linked to human disease, often associated with a vast genetic and clinical heterogeneity and further compounded by few genotype–phenotype correlations which help guide molecular genetic investigations.

Succinate dehydrogenase is a crucial metabolic enzyme complex that is involved in both the Krebs cycle and the mitochondrial respiratory chain. It is composed of two catalytic subunits (the flavoprotein SDHA, and Fe–S-containing SDHB) anchored to the inner mitochondrial membrane by the SDHC and SDHD subunits. All four subunits and the two known assembly factors are encoded by autosomal genes (SDHA, SDHB, SDHC, SDHD, SDHAF1 and SDHAF2, hereafter referred to as SDHx). Congenital recessive defects involving SDHx genes are associated with diverse clinical presentations, including leukodystrophy and cardiomyopathy (Alston et al. 2012).

A recent review describes SDHA mutations as the most common cause of isolated complex II deficiency, with 16 unique mutations reported in 30 patients (Ma et al. 2014;

Renkema et al. 2014); the next most common cause are mutations in SDHAF1, 4 mutations have been reported in 13 patients (Ghezzi et al. 2009; Ohlenbusch et al. 2012).

Just one mitochondrial disease patient is reported to harbour either SDHB (Alston et al. 2012) or SDHD (Jackson et al. 2014) mutations and metabolic presentations have yet to be reported in association with SDHC or SDHAF2.

In addition to their role in primary respiratory chain disease, SDHx mutations can act as drivers of neoplastic transformation following loss of heterozygosity (LOH). One of the most common causes of head and neck paraganglioma (HNPGL) is LOH at the SDHD locus. These mutations are inherited in a dominant manner with a parent of origin effect; typically only paternally inherited SDHD mutations are associated with HNPGL development (Hensen et al. 2011).