In this study, we subjected DNA from a PEO patient with unidentified genetic etiology to exome sequencing and detected a novel, homozygous missense variant in RRM2B
encodes p53-inducible ribonucleotide reductase small subunit 2-like protein (p53R2) and this protein plays an essential role in the maintenance of mtDNA by reducing ribonucleotides in the cytosol [17
], as is indicated by the fact that rare variants in this gene cause various forms of mitochondrial diseases characterized by mtDNA depletion and deletions. To our knowledge, 15 cases of mitochondrial depletion syndrome (MIM 612075) from 11 families [18
] and one sporadic case of mitochondrial neurogastrointestinal encephalopathy [23
] (MIM 603041) associated with homozygous or compound heterozygous rare variants in RRM2B
have been reported. More recently, two families with adPEO due to a heterozygous nonsense variant were described [24
]. In the screening of RRM2B
variants in 50 mitochondrial disease patients without causative variants in POLG1
, one Kearns-Sayre syndrome (MIM 530000) patient who carried two different novel missense variants and one PEO patient who carried an in-frame deletion were identified [25
The clinical symptoms and findings in the muscle biopsy of our case were typical for Mendelian-inherited PEO. No members of his maternal family have shown any neuromuscular symptoms, suggesting that the mtDNA deletions of the patient were not maternally inherited. Real-time quantitative PCR analysis revealed that there was no mtDNA depletion. We did not observe gastrointestinal dysmotility, cardiac conduction abnormalities, pancreatic dysfunction and sensory ataxic neuropathy, which are characteristic symptoms for other mitochondrial diseases associated with mtDNA deletions, namely mitochondrial neurogastrointestinal encephalopathy, Kearns-Sayre syndrome, Pearson syndrome, and sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (MIM 607459), respectively. Therefore, this patient was diagnosed as having arPEO caused by a homozygous missense variant of RRM2B.
Before this study, POLG1 had been the only established gene responsible for arPEO, while adPEO is a genetically heterogeneous disease, caused by rare variants in POLG1, POLG2, C10orf2, SLC25A4, OPA1 and RRM2B. The results of this study identifying the second responsible gene for arPEO indicate that arPEO is also a genetically heterogeneous disease, as is the case for adPEO.
The symptoms observed in this patient included major depressive episodes. Frequent comorbidity of mood disorders in patients of mitochondrial disease has been generally recognized [26
] and several lines of evidences have supported the possible involvement of mitochondrial dysfunctions in the pathophysiology of mood disorders [27
]. So far, rare variants of POLG1
have been reported in inherited PEO pedigrees with frequent comorbidity of mood disorders [28
]. Given the typical symptoms of major depressive disorder in the present case, RRM2B
should be added to the list of genes causal for PEO associated with mood disorders.
The identified P33S variant changes an amino acid residue highly conserved among vertebrates. The amino-terminal region of p53R2, in which this altered amino acid is located, is suggested to be crucial for interaction with p21 protein. p53R2 may contribute to DNA repair in cooperation with p21 [29
]. In its amino-terminal region, the homozygous p.R41P variant was detected in a mitochondrial depletion syndrome case [21
]. On the other hand, other pathogenic missense variants have been located in various sites of p53R2, including those involved in iron-binding [18
], those putatively crucial for homodimerization of p53R2 [21
] or heterotetramerization with the RRM1 (ribonucleoside-diphosphate reductase large subunit) homodimer [18
], and so on. The relationships between clinical phenotypes and the properties of variants, as well as their underlying mechanisms, should be the subject of further investigations.