A novel mutation in COQ2 leading to fatal infantile multisystem disease

https://doi.org/10.1016/j.jns.2013.01.004Get rights and content

Abstract

Coenzyme Q10 (ubiquinone or CoQ10) serves as a redox carrier in the mitochondrial oxidative phosphorylation system. The reduced form of this lipid-soluble antioxidant (ubiquinol) is involved in other metabolic processes as well, such as preventing reactive oxygen species (ROS) induced damage from the mitochondrial membrane. Primary coenzyme Q10 deficiency is a rare, autosomal recessive disorder, often presenting with neurological and/or muscle involvement. Until now, five patients from four families have been described with primary coenzyme Q10 deficiency due to mutations in COQ2 encoding para-hydroxybenzoate polyprenyl transferase. Interestingly, four of these patients showed a distinctive renal involvement (focal segmental glomerular sclerosis, crescentic glomerulonephritis, nephrotic syndrome), which is only very rarely seen in correlation with mitochondrial disorders. The fifth patient deceases due to infantile multi organ failure, also with renal involvement. Here we report a novel homozygous mutation in COQ2 (c.905C>T, p.Ala302Val) in a dizygotic twin from consanguineous Turkish parents. The children were born prematurely and died at the age of five and six months, respectively, after an undulating disease course involving apneas, seizures, feeding problems and generalized edema, alternating with relative stable periods without the need of artificial ventilation. There was no evidence for renal involvement. We would like to raise awareness for this potentially treatable disorder which could be under diagnosed in patients with fatal neonatal or infantile multi-organ disease.

Introduction

The CoQ10 biosynthetic pathway has been extensively studies in yeast (Saccharomyces cerevisiae) and involves at least ten different proteins to produce CoQ10 in mitochondria [1]. The human orthologs of the corresponding yeast genes have all been identified [2]. An essential step in the biosynthesis of CoQ10 is catalyzed by the enzyme parahydroxybenzoate polyprenyl transferase (E.C. 2.5.1.39) which condensates the parahydroxybenzoate ring, derived from the tyrosine or phenylalanine, with the 10-isoprenoid chain arising from mevalonate, a precursor in cholesterol biosynthesis [3]. The formed prenylated parahydroxybenzoate is subsequently hydroxylated, methylated, O-methylated and finally decarboxylated to form coenzyme CoQ10. One of the main functions of CoQ10 in the mitochondrial respiratory chain is to shuttle electrons from complex I (NADH dehydrogenase) and complex II (succinate dehydrogenase) to complex III (the bc1 complex). In addition, CoQ10 functions as an endogenous antioxidant in plasma membranes and lysosomes, and can act as a modulator of apoptosis [4]. In healthy individuals, the biosynthetic pathway produces sufficient amounts of CoQ10, although in some diseases and during aging CoQ10 levels decrease to a variable extent [5], [6], [7]. By contrast, genetic defects leading to a dysfunction of the biosynthetic pathway can result in a deficiency of CoQ10, leading to a disease with a variable phenotype. In 1989, Ogasahara and colleagues reported the first case of primary CoQ10 deficiency in skeletal muscle [8]. Currently, more than 100 patients with CoQ10 deficiency have been reported. These can be subdivided into five main groups based on the clinical manifestations (for review see [9]; mutated genes between brackets): (1) encephalomyopathy (COQ4) [10], (2) isolated myopathy (ETFDH), (3) nephropathy (COQ2, COQ6), (4) infantile multisystem disease (COQ2, PDSS2, COQ9, PDSS1, COQ6), (5) cerebellar ataxia (ADCK, APTX). It should be mentioned that ETFDH and APTX lead to secondary CoQ10 deficiency and should not be regarded as a primary CoQ10 deficiency.

The first mutation in a gene involved in the CoQ10 pathway was identified in 2006 in the COQ2 gene encoding p-hydroxybenzoate-polyprenyltransferase (EC 2.5.1.39) using homozygosity mapping in two siblings with infantile onset encephalomyopathy and nephrotic syndrome [11]. Human COQ2 gene is located on chromosome 4q21, consists of seven exons and encodes a protein of 421 amino acids. Since then only three more patients from three families with mutations in COQ2 have been reported in the literature [12], [13], [14]. Here we report a novel homozygous mutation in the COQ2 gene of a twin boy and girl from healthy first grade consanguineous Turkish parents. In contrast to the previously reported patients our patient seems to have no renal involvement.

Section snippets

Patients and methods

See Table 1 for a summary of the clinical data of our patients and the patients reported in literature.

Biochemical measurements

Biochemical investigations performed in a skeletal muscle biopsy from the male patient showed a severely reduced oxidation rate of [1-14C] pyruvate in the presence of malate, while the oxidation rate of [1-14C] pyruvate in the presence of carnitine was less severely reduced (Table 2). This combination of oxidation rate abnormalities is suggestive for a deficiency of the oxidative phosphorylation system [16]. In addition, the production rate of ATP from the oxidation of pyruvate + malate was

Discussion

Here we describe a new pathogenic mutation (c.905C>T (p.Ala302Val)) in COQ2 leading to primary CoQ10 deficiency in a Turkish dizygotic twin pair. The pathogenicity is supported by several observations. Both patients showed reduced CoQ10 levels in muscle tissue, although the residual levels are quite different between the two patients. This might be explained by the fact that CoQ10 levels are influenced by many factors, such as the diet [27]. In addition, both patients show a reduced activity of

Conflicts of interests

There are no conflicts of interest.

Acknowledgments

We thank Dr. C. Quinzii for the primer sequences of the COQ2 gene. We are grateful to the technicians of the tissue culture lab and the muscle lab of the NCMD at the LGEM laboratory for excellent technical assistance. We acknowledge Hans van Bokhoven and Ellen van Beusekom for their generous gift of Turkish control samples.

References (31)

  • C. Parrado-Fernandez et al.

    Calorie restriction modifies ubiquinone and COQ transcript levels in mouse tissues

    Free Radic Biol Med

    (2011)
  • A.J. Lambert et al.

    Inhibitors of the quinone-binding site allow rapid superoxide production from mitochondrial NADH:ubiquinone oxidoreductase (complex I)

    J Biol Chem

    (2004)
  • M. Kawamukai

    Biosynthesis and bioproduction of coenzyme Q10 by yeasts and other organisms

    Biotechnol Appl Biochem

    (2009)
  • C.M. Quinzii et al.

    Coenzyme Q and mitochondrial disease

    Dev Disabil Res Rev

    (2010)
  • M. Forsgren et al.

    Isolation and functional expression of human COQ2, a gene encoding a polyprenyl transferase involved in the synthesis of CoQ

    Biochem J

    (2004)
  • Cited by (44)

    • Retinitis pigmentosa with optic neuropathy and COQ2 mutations: A case report

      2022, American Journal of Ophthalmology Case Reports
      Citation Excerpt :

      Deficiency of CoQ10 manifests with various clinical presentations. For example, in the case of COQ2 mutation, multiple system atrophy, encephalomyopathy, ataxia, lactic acidosis, deafness, RP, optic atrophy, myopathy, and steroid-resistant nephrotic syndrome have been reported with various combinations.7,12,22–25 Two siblings (71 and 66 years old) presented with multiple system atrophy and RP7 A 33-month-old boy suffering from optic atrophy in addition to encephalomyopathy and nephropathy has been reported12 However, the detailed ocular features were not described in these reports.

    • Primary Coenzyme Q deficiencies: A literature review and online platform of clinical features to uncover genotype-phenotype correlations

      2021, Free Radical Biology and Medicine
      Citation Excerpt :

      Particularly, all the three COQ2 patients reported to have respiratory symptoms were born prematurely and presented with a multisystemic involvement; one also showed HCM. When sorted by age at onset, patients with the earliest onset (group 1) first presented with a broad spectrum of different symptoms (SRNS (5/13, 38%) [152,153], respiratory defects (3/13, 23%) [151,191], DM (4/13, 31%) [153], liver failure (1/13, 8%) [152], Sz (1/13, 8%) [192], acidosis (1/13, 8%) [213], collapse (1/13, 8%) [152] or hyperreactivity (1/13, 8%) [213]) (Fig. 8C). For group 2 patients, SRNS was the first symptom in the majority of the cases (5/6, 83%) [113,121,136,150,154,200].

    • Biochemistry of Mitochondrial Coenzyme Q Biosynthesis

      2017, Trends in Biochemical Sciences
    • Novel recessive mutations in COQ4 cause severe infantile cardiomyopathy and encephalopathy associated with CoQ<inf>10</inf> deficiency

      2017, Molecular Genetics and Metabolism Reports
      Citation Excerpt :

      It is intriguing that although all of these gene products function in the same pathway to synthesize CoQ10, their clinical presentations are quite distinct. For example, mutations in PDSS2, encoding for one of the two subunits of COQ1 (the first committed enzyme in the CoQ10 biosynthetic pathway) have been reported in an infant with severe Leigh's syndrome, nephrotic syndrome and CoQ10 deficiency [10], whereas autosomal recessive mutations in COQ2, encoding for the para-hydroxybenzoate-polyprenyl transferase (the second committed enzyme in the pathway) was reported in patients with variable clinical presentation of the multisystem infantile form of CoQ10 deficiency or isolated nephropathy [13,14,26–28]. It is tempting to speculate that this clinical heterogeneity may reflect specific problem associated with defects at different steps in the CoQ10 biosynthetic pathway.

    View all citing articles on Scopus
    1

    Equal contribution.

    View full text