Mitochondrial neurogastrointestinal encephalopathy due to mutations in RRM2B

Abstract

Background: Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a progressive neurodegenerative disorder associated with thymidine phosphorylase deficiency resulting in high levels of plasma thymidine and a characteristic clinical phenotype.

Objective: To investigate the molecular basis of MNGIE in a patient with a normal plasma thymidine level.

Design: Clinical, neurophysiological, and histopathological examinations as well as molecular and genetic analyses.

Setting: Nerve and muscle center and genetic clinic. Patient A 42-year-old woman with clinical findings strongly suggestive for MNGIE.

Main outcome measures: Clinical description of the disease and its novel genetic cause.

Results: Identification of mitochondrial DNA depletion in muscle samples (approximately 12% of the control mean content) prompted us to look for other causes of our patient's condition. Sequencing of genes associated with mitochondrial DNA depletion-POLG, PEO1, ANT1, SUCLG1, and SUCLA2-did not reveal deleterious mutations. Results of sequencing and array comparative genomic hybridization of the mitochondrial DNA for point mutations and deletions in blood and muscle were negative. Sequencing of RRM2B, a gene encoding cytosolic p53-inducible ribonucleoside reductase small subunit (RIR2B), revealed 2 pathogenic mutations, c.329G>A (p.R110H) and c.362G>A (p.R121H). These mutations are predicted to affect the docking interface of the RIR2B homodimer and likely result in impaired enzyme activity.

Conclusions: This study expands the clinical spectrum of impaired RIR2B function, challenges the notion of locus homogeneity of MNGIE, and sheds light on the pathogenesis of conditions involved in the homeostasis of the mitochondrial nucleotide pool. Our findings suggest that patients with MNGIE who have normal thymidine levels should be tested for RRM2B mutations.

Figures

Figure 1

Axial fluid-attenuated inversion recovery, T2-weighted magnetic resonance images of the brain showing symmetric, hyperintense, nonenhancing lesions in the basal ganglia (arrows) (A) and patchy signals throughout the white matter (arrows) (B).

Figure 2

Muscle biopsy suggestive of mitochondrial dysfunction. A, Decreased cytochrome-c oxidase staining (original magnification ×100). B, Modified Gomori trichrome staining showing a ragged red fiber (original magnification ×400). Mild variation in fiber size is seen. C, Succinate dehydrogenase staining showing multiple ragged blue fibers (original magnification ×40). These findings were suggestive of the mitochondrial dysfunction. Other findings included rare denervated fibers and several small fiber-type groups (data not shown).

Figure 3

Consequences of the R110H and R121H mutations on the structure of the ribonucleoside reductase small subunit (RIR2B). R110H and R121H (in red) are within 0.75 nm of each other and straddle the outlined homodimer interface. Each has 13 structural neighbors (light green) that overlap at F111, S112, Q113, and E114 (dark green). The few instances of homologs carrying the R110H substitution have at best only 6 identical structural neighbors (N106, L107, E109, F111, E114, and R186), and the homologs with the R121H substitution have at best just 1 identical structural neighbor (Y124). The figure was generated by using the PyMOL program (DeLano Scientific LLC, Palo Alto, California) and the 2vux Protein Data Bank file (doi:10.2210/pdb2vux/pdb).