RRM2B

MedlinePlus Genetics provides information about Mitochondrial neurogastrointestinal encephalopathy disease

At least 17 mutations in the RRM2B gene have been identified in people with an eye condition called progressive external ophthalmoplegia. This disorder weakens the muscles that control eye movement and causes the eyelids to droop (ptosis). Some affected individuals have additional signs and symptoms, such as weakness of other muscles, extreme tiredness (fatigue), hearing loss caused by problems with the inner ear (sensorineural hearing loss), and digestive problems.

Typically, mutations that cause progressive external ophthalmoplegia occur in one copy of the RRM2B gene, although rarely both copies of the gene are altered. RRM2B gene mutations associated with progressive external ophthalmoplegia lead to impaired RNR activity. These mutations result in large deletions of genetic material from mtDNA in muscle tissue, possibly because impairment of RNR activity leads to a shortage of nucleotides, although the mechanism is unclear. Researchers have not determined how deletions of mtDNA lead to the specific signs and symptoms of progressive external ophthalmoplegia, although the features of the condition may be related to impaired oxidative phosphorylation. It has been suggested that eye muscles are commonly affected by mitochondrial defects because they are especially dependent on oxidative phosphorylation for energy.

More than a dozen mutations in the RRM2B gene can cause RRM2B-related mitochondrial DNA depletion syndrome, encephalomyopathic form with renal tubulopathy (RRM2B-MDS), a severe condition that affects multiple body systems. It typically leads to brain dysfunction combined with muscle weakness (encephalomyopathy) and a problem with kidney function known as renal tubulopathy. The mutations that cause this disorder occur in both copies of the RRM2B gene. They reduce the activity or amount of RNR, which likely impairs production of mtDNA nucleotides. A shortage of nucleotides available for the production of mtDNA molecules leads to a reduction in the amount of mtDNA (known as mtDNA depletion) and impairs mitochondrial function in many different types of cells.

Impairment of oxidative phosphorylation is thought to underlie the signs and symptoms of mitochondrial DNA depletion syndrome. It is unclear why some RRM2B gene mutations result in deletions of genetic material from mtDNA (as in progressive external ophthalmoplegia, described above) and others reduce the overall amount of mtDNA (as in RRM2B-MDS).