COQ2 Nephropathy: A Newly Described Inherited Mitochondriopathy with Primary Renal Involvement : Journal of the American Society of Nephrology

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COQ2 Nephropathy

A Newly Described Inherited Mitochondriopathy with Primary Renal Involvement

Diomedi-Camassei, Francesca*; Di Giandomenico, Silvia; Santorelli, Filippo M.; Caridi, Gianluca§; Piemonte, Fiorella; Montini, Giovanni; Ghiggeri, Gian Marco§; Murer, Luisa; Barisoni, Laura; Pastore, Anna; Muda, Andrea Onetti††; Valente, Maria Luisa**; Bertini, Enrico; Emma, Francesco‡‡

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Journal of the American Society of Nephrology 18(10):p 2773-2780, October 2007. | DOI: 10.1681/ASN.2006080833
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Coenzyme Q10 (CoQ10; ubiquinone) is an essential component of the mitochondrial electron-transport chain and a lipid-soluble antioxidant molecule.14 In the mitochondrial respiratory chain, CoQ10 accepts reducing equivalents from NADH in complex I and acts as an electron shuttle between complex II and complex III.5,6 In addition, its reduced form, also termed ubiquinol, protects membrane phospholipids and serum lipoprotein from lipid peroxidation and prevents mitochondrial membrane protein from oxidative damage induced by reactive oxygen species.4,7

The biochemical pathway of CoQ10 synthesis is complex and has not yet been completely elucidated. It involves at least 10 different enzymes that have been isolated from various genomes and are termed COQ1 through COQ10.8,9

Primary CoQ10 deficiency has been reported in a group of rare autosomal recessive disorders that are generally characterized by different combinations of central nervous system, skeletal muscle, and peripheral nerve clinical symptoms.919 Early diagnosis is crucial, because oral supplementation with CoQ10 has been shown to improve clinical symptoms.2022

COQ2 is part of the CoQ10 pathway and encodes the parahydroxybenzoate-polyprenyltransferase (EC, which catalyzes the prenylation of parahydroxybenzoate with a polyprenyl group.2 Mutations in the COQ2 gene first were identified in two siblings with primary CoQ10 deficiency,8 and another child was recently reported.23 One sibling of the former report presented with progressive encephalomyopathy and steroid-resistant nephrotic syndrome (NS), whereas his younger sister presented with isolated NS.8,22 Herein, we described the renal pathology of these cases and two additional, unrelated patients who bore new inherited COQ2 mutations and presented with steroid-resistant NS or neonatal renal failure.


Clinical History

Patient 1 is a 22-mo-old boy who was born after an uneventful pregnancy to unrelated healthy parents who originated from Eastern Europe. Family history is unremarkable. A 6-yr-old brother is healthy. At 18 mo of age, the patient rapidly developed severe steroid-resistant NS. Serology for hepatitis B, hepatitis C, Epstein-Barr virus, HIV, and parvovirus B19 was negative. Serum lactate was normal. The renal pathology revealed a collapsing glomerulopathy for which angiotensin-converting enzyme inhibitor and indomethacin treatment was started. The NS, however, continued to worsen, leading to severe anasarca that was unresponsive to infusions of human albumin. Six weeks after the initial symptoms, he underwent a unilateral nephrectomy and began peritoneal dialysis. Remarkably, he had no signs of neuromuscular involvement. Electroencephalogram and brain MRI were also normal. At 21 mo of age, a muscle biopsy was obtained. Since that age, the patient is receiving oral supplementation of CoQ10 (30 mg/kg per d). His neurologic examination remains completely normal after 8-mo of follow-up.

Patient 2 was a 6-mo-old boy born from distantly related healthy parents who originated from a small village in southern Italy. Pregnancy was complicated by oligohydramnios at the end of gestation. At 5 d of life, the patient was found to be severely oliguric and hypertensive. At 10 d of life, a surgical renal biopsy demonstrated severe crescentic glomerulonephritis. Aggressive prednisone treatment failed to improve renal function, and peritoneal dialysis was started at 3 wk of age. At 3 mo of age, he developed drug-resistant seizures that evolved into a status epilepticus. Thereafter, his encephalopathy continued to worsen, leading to a state of unresponsiveness, hypotonia, respiratory failure, and death at the age of 6 mo. Brain MRI showed cortical and subcortical stroke-like lesions in the frontal, insular, and temporal regions and signs of diffuse cerebral atrophy. MRI spectroscopy revealed a significant peak of lactate in multiple single voxels, corresponding to the frontal cortex and basal ganglia. Increased lactate levels were also documented in the cerebrospinal fluid (106 mg/dl; normal value 10 to 22). In the urine, organic acid analysis showed a marked increase in lactate and pyruvate excretion. Serum lactate levels were normal. Serum ammonium levels were moderately increased (86 μmol/L; normal value 22 to 55). Serology for hepatitis B, hepatitis C, Epstein-Barr virus, HIV, rubella, cytomegalovirus, and toxoplasma gondii was negative. The family history is remarkable for an older sister who had died of acute respiratory distress and metabolic acidosis at 18 h of life. Of note, her serum ammonium levels had been elevated (520 μmol/L) shortly after birth. The eldest sister, now aged 6 yr, is healthy.

Patients 3 and 4 have been previously reported.8,9,22 Briefly, they were born from consanguineous parents who originated from north Africa. Patient 3 presented in the first year of life with nystagmus secondary to bilateral optic nerve atrophy, seizures, and developmental delay. At 12 mo of age, he developed severe steroid-resistant NS secondary to FSGS, which progressed to end-stage renal failure during a period of 6 mo. He received a successful transplant at the age of 3 yr. His younger sister (patient 4) developed NS secondary to FSGS at 12 mo of life without any clinical signs of neurologic involvement.8

Genetic Analyses

No mutations in the NPHS1, NPHS2, and PDSS2 genes were detected in patients 1 and 2. Patient 1 showed a combined heterozygous COQ2 mutation. He inherited a c.590G→A (p.Arg197His) mutation from his mother and a c.683A→G (p.Asn228Ser) mutation from his father. His healthy brother carries the paternal mutation. Patient 2 harbored a homozygous c.437G→A (p.Ser146Asn) COQ2 mutation. Both parents are heterozygous carriers. These new mutations were not detected in 500 control chromosomes. The c.890 A→G mutation (p.Tyr297Cys) in patients 3 and 4 has been reported elsewhere.8,22

The newly identified mutations, as well as the variant detected before affect amino acid residues that are highly preserved in mammal, fly, worm, and yeast (Figure 1).8,9 On the basis of the predicted structure of the protein,2 the mutation in patient 2 is located 26 amino acids upstream of the putative substrate-binding site (UbiA), the Arg197His mutation of patient 1 is located three amino acids downstream of the same domain, and the Asn228Ser mutation is located in the first putative transmembrane domain. The mutation detected in patients 3 and 4 is predicted to be located in the third putative transmembrane domain.8

Microscopic Features

Patient 1.

Examination of the renal biopsy revealed marked podocyte hypertrophy and hyperplasia forming pseudocrescents and wrinkling of the glomerular basement membranes (GBM) consistent with collapsing glomerulopathy. No immunecomplex deposition was detected. The tubulointerstitial compartment revealed extensive microcyst formation, focal tubular atrophy, and interstitial fibrosis. On ultrastructural examination, podocytes were characterized by extensive foot process effacement, partial loss of primary processes, and marked hypertrophy. Podocyte cell bodies were filled with numerous dysmorphic mitochondria, lacking cristae, or with abnormally enlarged ones and an electron-lucent central core. Dysmorphic mitochondria were also present in other glomerular cells, including parietal, endothelial, and mesangial cells, and in myocytes of small arteries, interstitial fibroblasts, and tubular epithelial cells. No electron-dense deposits or tubuloreticular inclusions were identified. A fragment of skeletal muscle was also examined and revealed accumulation of periodic acid-Schiff–positive granules at the periphery of the myocytes, underneath the sarcolemma (ragged red fibers). Occasionally, myocytes lost their typical striate appearance or appeared pale and small, indicating atrophy (Figure 2).

Patient 2.

Analysis of the renal biopsy revealed severe extracapillary proliferation, occasionally positive for fibrinogen, with collapse of the GBM. There was no evidence of immune complex deposition by immunofluorescence or electron microscopy. On ultrastructural analysis, podocytes and parietal epithelial cells were filled with numerous dysmorphic mitochondria, which were variable in shape and size, often enlarged, had an electron-lucent core, and contained few short cristae.

Patients 3 and 4.

Patients 3 and 4 had classic FSGS lesions on renal biopsy, with segmental solidification of the tuft, adhesion of the tuft to the Bowman's capsule, and occasional accumulation of hyaline material. Sclerosing lesions in patient 3 were more extensive than in his sister (patient 4). Ultrastructural studies showed diffuse effacement of foot processes, osmiophilic depositions in the subendothelial space, swelling of endothelial cells, and increase in mesangial matrix. In both patients, numerous and abnormal mitochondria were present and were characterized by an oncocytic-like aspect. Podocyte mitochondrial proliferation extended also to fibroblasts and endothelial, mesangial, and tubular cells in patient 3; it was limited to glomerular cells in patient 4.


Renal cortex of patients 1 and 2 showed marked decrease in tubular cytochrome C oxidase (COX) and succinate dehydrogenase (SDH) activity, when compared with control specimens. SDH and COX histochemistry in skeletal muscle of the same patients demonstrated a reaction homogeneity between type 1 and type 2 fibers and mildly increased staining, indicating mitochondrial proliferation. Lipid content was not increased (Figure 3).

Mitochondrial Respiratory Chain Complexes and Measurements of CoQ10 Levels

Results of biochemical analyses in renal cortex and skeletal muscle of patients 1 and 2 are reported in Figure 4 and Table 1. As shown, complexes II and III activities were in the low level of the reference range or moderately decreased. The combined complex [II+III] activity was more severely decreased, suggesting ubiquinone depletion. This was confirmed by direct measurement of CoQ10 levels, which were markedly reduced. Low levels of complexes I, II, and IV activities were also observed.


Renal dysfunction associated with mitochondriopathies is generally a rare event. Three cases of ubiquinone deficiency that presented with central and peripheral nervous system involvement and was associated with NS secondary to FSGS in the first decade of life were previously reported in the literature.21 Although primary CoQ10 deficiencies have been recognized since the late 1980s, no mutation had been described in the ubiquinone synthesis genes until recently.8,19

We identified two novel COQ2 mutations and analyzed the renal pathology of all currently reported patients. The pathogenicity of these mutations is supported by their absence in 500 control DNA samples, the ultrastructural finding of abnormal mitochondria proliferation, and the demonstration of low CoQ10 levels in examined tissues (Table 2). In addition, Lopez-Martin et al.9 recently gave functional support to our clinical and pathologic observation showing that COQ2 cDNA harboring the Tyr297Cys mutation of patients 3 and 4 is unable to complement functionally COQ2-deficient yeast strains, as opposed to the wild-type cDNA. These authors also showed that when the same mutation is introduced in the wild-type COQ2 yeast gene, CoQ6 concentrations decrease and colony growth in respiratory chain–dependent medium is markedly reduced.

Taken together, these data allow identification of a new entity within the category of mitochondrial cytopathies, characterized by inherited COQ2 mutations, proliferation of dysmorphic mitochondria, and primary glomerular damage. We propose to refer to this entity as “COQ2 nephropathy,” because the kidney seems to be a primary target, as illustrated by the fact that two of the reported patients presented with isolated renal symptoms (four additional patients with CoQ10 deficiency but without renal involvement were screened and no COQ2 and PDSS2 mutations were found). This finding was somewhat surprising, because CoQ10 is ubiquitously expressed but may be related to high CoQ10 content in human kidney.3 On the contrary, residual coenzyme activity may have prevented cell damage in other organs, as suggested by CoQ10 muscular levels in patient 1, which were marginally reduced. Dietary uptake may have also provided enough ubiquinone to overcome impaired CoQ10 synthesis in some tissues.3 However, the prevalence of renal symptoms in COQ2 defects may be related to differential expression of proteins involved in ubiquinone metabolism.3 In support of this hypothesis, we did not detect COQ2 mutations in four different patients with congenital ataxia, severe CoQ10 deficiency, and no glomerular involvement, as stated before (data not shown).

A prominent aspect of “COQ2 nephropathy” is the heterogeneous pattern of glomerular lesions (Table 2, Figure 2). Ultimately, all reported lesions could be related to visceral epithelial cell damage, as illustrated by the unifying finding of abnormal mitochondria proliferation in these cells.

FSGS lesions similar to those found in patients 3 and 4 have already been associated with mutations in the mitochondrial genome [3243A→G in the tRNALeu(UUR) gene], which may cause isolated glomerular disease.6,2426 Podocyte damage secondary to inherited mitochondrial dysfunction may cause visceral cell depletion, accumulation of extracellular matrix, and ultimately sclerosis of the glomerular tuft.27 In other cases, the same mitochondrial disease seems to trigger epithelial cell proliferation (in particular podocyte proliferation), associated with GBM collapse. Whereas increased apoptosis of podocyte cells may explain the mechanisms underlying FSGS formation in mitochondrial cytopathies,28 it remains unclear why in some cases the pathway taken by injured podocytes leads to proliferative lesions.29

The collapsing lesions described in patient 1 are comparable to those described in a murine model of collapsing glomerulopathy (kd/kd), in which animals spontaneously develop proteinuria and renal disease associated with the presence of numerous dysmorphic mitochondria in all cell types, including podocytes.30 In this model, mitochondrial dysfunction is due to a mutation in the gene encoding for a prenyltransferase-like mitochondrial protein that has extensive homologies with the human transprenyltransferase (PDSS2) gene, which is involved in the CoQ10 synthesis pathway.31 Mutations in PDSS2 were not detected in patients 1 and 2 but were recently reported in one patient who presented with severe Leigh syndrome and NS associated with CoQ10 deficiency.19

Conversely, patient 2 presented with acute renal failure secondary to extracapillary proliferation, indicating that cells involved in this process included parietal epithelial cells in addition to podocytes. Renal lesions were remarkable by their advanced stage at 10 d of life, indicating strongly that they had developed in utero. This is also suggested by the obstetric report indicating oligohydramnios during the last weeks of gestation.

Biochemically, these lesions are characterized by a moderate reduction of complex II and complex III activities in renal and muscle tissues and by a remarkable reduction of their combined, ubiquinone-dependent [II+III] activity (Figure 4, Table 1). Direct CoQ10 measurements confirm these functional data. The histochemical analyses, however, show discordant results between kidney and muscle. In skeletal muscles, high SDH activity is an indicator of increased mitochondria number. Conversely, renal SDH activity was decreased, despite equally intense mitochondrial proliferation. This seeming discrepancy may indicate more severe mitochondrial injury in the kidney. In this tissue, ubiquinol depletion may have increased reactive oxygen species activity,4 causing damage of inner membrane enzymes, such as SDH.4 SDH has been shown to be particularly sensitive to oxidative stresses in comparison with other enzymes of the Krebs cycle and electron transport chain complexes.32 The decreased activities of other respiratory chain complexes observed in our patients may be related to similar mechanisms of mitochondrial damage.

Mitochondrial dysfunction and altered mitochondrial gene expression have also been documented in patients with NS secondary to nephrin mutations,33,34 suggesting that, regardless of the initial insult, mitochondria play an important role in podocyte metabolism and may be actively involved in the pathophysiology of various forms of NS.

In conclusion, COQ2 mutations cause a renal disease that is characterized by variable renal lesions and widespread proliferation of dysmorphic mitochondria in glomerular cells. The clinical picture can be heterogeneous, and neuromuscular symptoms may complicate the course of the disease. Early recognition of this new entity may be crucial, because clinical symptoms can improve after ubiquinone supplementation, and neurologic complications may be prevented.8,9,21,22 Long-term follow-up is needed to define the ultimate prognosis of these patients.


Histology, Immunofluorescence, and Histochemistry

Formalin-fixed renal specimens were embedded in paraffin and stained with hematoxylin and eosin, periodic acid-Schiff, trichrome, and periodic acid-methenamine silver stains using standard techniques. Frozen renal tissues were immunostained with antibodies directed against IgA, IgG, IgM, C3, C1q, C4d, fibrinogen, and albumin. Electron microscopy was performed on glutaraldehyde-fixed tissues and processed for ultrastructural analysis according to standard laboratory protocols. In patients 1 and 2, 5-μm frozen sections from muscle and kidney were incubated with cytochrome C and diaminobenzidine or with succinate and nitroblue-tetrazolium to assess the activities of COX and SDH, respectively, following established protocols.35

Biochemical Analysis

Spectrophotometric measurements of mitochondrial respiratory chain enzyme activities and citrate synthase activity were performed on renal cortex and muscle tissues as previously reported.36 CoQ10 concentrations were assayed by reverse-phase HPLC according to established protocols.37 Normal values for skeletal muscles have been established in our laboratory.37 No reference data are available for the renal cortex; therefore, values from patients were compared with 13 pediatric control specimens that were obtained after surgical nephrectomy for nephroblastoma. Parenchymal integrity was checked by standard light microscopy techniques. Particular attention was paid to analyze samples containing only renal cortex.

Molecular Genetics

Genomic DNA was purified from peripheral blood. Screening for mutations in the nephrin and podocin genes (NPHS1 and NPHS2) was performed as previously reported.38 Direct sequencing after PCR amplification was used to screen for mutation in the COQ2 (GenBank no. NM_015697) and PDSS2 genes (GenBank no. NM_020381). All analyses were performed using standard techniques with BigDye 3.1 chemistry, following the manufacturer's protocols (Applied Biosystems, Foster City, CA). Intronic oligonucleotide primers sequences are available upon request.



Figure 1:
Sequence homologies between COQ2 homologue genes of close and distantly related species. Patients’ mutations are indicated by arrows. Conservative mutations are indicated with gray characters; nonconservative mutations are indicated with nonbold letters.
Figure 2:
Renal histology and ultrastructural findings. Numbers correspond to the patient numbers, as used in the text. Left panels show light microscopy. Right panels show a representative visceral epithelial cell by electron microscopy (EM). In all cases, intense mitochondrial proliferation was observed. P1, Collapsed capillary tuft, surrounded by hyperplastic podocytes (silver stain). EM image shows wrinkling and folding of the GBM and enlarged podocytes containing numerous dysmorphic mitochondria. P2, Extracapillary proliferation with collapse of the glomerular tuft. Tubular structures show mild degenerative changes of epithelial cells and contain abundant cellular debris (periodic acid-Schiff [PAS] stain). EM image shows numerous dysmorphic mitochondria in the cytoplasm of podocytes. P3, FSGS lesion with partial sclerosis of the capillary tuft and mild tubular dilation (PAS stain). EM image shows folded and collapsed GBM and swollen podocyte cell containing numerous dysmorphic mitochondria. Diffuse pedicle fusion and microvillous transformation of cellular profile are evident. P4, Mild FSGS lesions and tubular dilation (hematoxylin and eosin stain). EM image shows numerous mitochondria in the cytoplasm of visceral epithelial cells that have a oncocyte-like feature and shows diffuse pedicle fusion and microvillous transformation of cellular membrane. Magnifications: ×40 in P1; ×20 in P2, P3, and P4.
Figure 3:
Kidney and muscle histochemistry. P, patient; C, control tissues (from age-matched children); M, skeletal muscle; K, kidney. Skeletal muscle SDH and COX histochemistry shows loss of type 1/type 2 fiber heterogeneity and mildly increased staining, which suggests mitochondrial proliferation. Renal SDH and COX histochemistry shows markedly decreased tubular activity. Magnifications: ×40 in muscle; ×20 in kidney.
Figure 4:
Biochemical data. Biochemical measurements in renal cortex (top) and muscle (bottom) homogenates. Complex I through IV values are expressed as unit per the activity of citrate synthase (CS). CS is expressed as nmol/min per mg protein; CoQ10 is expressed as μmol/g tissue. Gray areas indicate control values. Reference values for skeletal muscle were obtained from 52 control samples and for renal cortex were obtained from 13 control samples (both indicated as third, 50th, and 97th percentiles). •, patient 1; ▴, patient 2.
Table 1:
Biochemical data (absolute values)a
Table 2:
Clinical, pathological, biochemical, and genetic features of reported patientsa

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