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Official Full Name
chromosome 12 open reading frame 65
COXPD7; C12orf65; chromosome 12 open reading frame 65; CL065_HUMAN; mitochondrial; Probable peptide chain release factor C12orf65; probable peptide chain release factor C12orf65, mitochondrial; SPG55

Recent Research Progress

The C12orf65 gene at 12q24.31 encodes a soluble mitochondrial matrix protein belonging to the class I peptide chain release factors (RFs) family containing a GGQ motif (Gly-Gly-Gln motif) in the translation termination. The mitochondrial translation machinery in eukaryotic cells results in the biosynthesis of 13 polypeptides that are involved in oxidative phosphorylation. Mitochondrial ribosomes have three transfer RNA (tRNA)-binding sites of the A (aminoacyl), P (peptidyl) and E (exit) sites that bind to their respective tRNAs on messenger RNAs. When a mitochondrial stop codon (UAA or UAG) is recognized at the A site of the ribosome, RF interacts with the peptidyl transferase center of the large ribosomal subunit via its GGQ motif. This conformation triggers peptidyl-tRNA hydrolysis, which catalyzes the hydrolysis of the ester bond between the nascent polypeptide and the peptidyl-tRNA. The C12orf65 mutation impairs the oxidative phosphorylation system, resulting in variable phenotypes such as mitochondrial diseases. It has been reported that knockdown of C12orf65 leads to mitochondrial translation defect with increased reactive oxygen species production, reduced cellular proliferation and apoptosis.

C12orf65 gene mutation leads to recessive form of Charcot–Marie Tooth disease type 6 (CMT6)

The association of neuropathy and optic atrophy (also known as CMT6) with autologous dominant, recessive and X-linked genetic patterns has been described. Mutations in Mitofusin 2 have been found to result in dominant forms of CMT6. The phosphoribosyl pyrophosphate synthase-I mutation leads to X-linked CMT6, but until now, mutations in the form of recessive disease have never been identified. Arianna Tucc et al. described a large close relative family with neuropathy and optic atrophy carrying a loss-of-function mutation in the C12orf65 gene. They reported mitochondrial damage in patient cell lines, followed by a variety of evidences which include reduction in complex V activity and stability (blue native gel assay), decrease in mitochondrial respiratory rate and reduction in mitochondrial membrane potential. That study describes a mutation in the C12orf65 gene that leads to a recessive form of CMT6 and confirms the role of mitochondrial dysfunction in this complex axonal neuropathy.

C12orf65 gene mutation causes combined oxidative phosphorylation defectcy type 7 (COXPD7)

COXPD7 is a rare mitochondrial metabolic disorder that causes optic atrophy and Leigh syndrome-like disease. C12orf65 encodes mitochondrial matrix proteins, which are essential for releasing newly synthesized proteins from mitochondrial ribosomes. Loss of function damages the translation of mitochondrial proteins, resulting in a reduction of the protein complexes necessary for efficient oxidative phosphorylate.

C12orf65 is an important pathogenic gene in Behr’s syndrome

Behr’s syndrome is a classical phenotypic description of childhood optic atrophy combined with various neurological symptoms, including eyelids, nystagmus, spastic lower extremity spasm, ataxia, peripheral neuropathy and learning difficulties. Angela Pyle et al. detected two different homozygous C12orf65 nonsense mutations in four patients, and their clinical manifestations were consistent with the historical description of Behr syndrome. The first symptom of all patients was childhood optic atrophy, followed by spastic lower extremity paralysis, distal weakness, motor neuropathy and eye spasm. They argue that C12orf65 mutations are more frequent than previously suggested and screening of this gene should be considered not only in patients with mitochondrial respiratory chain defects, but also in patients with inherited peripheral neuropathy, spastic paraplegia and ataxia, especially in patients with pre-existing optic atrophy.

In summary, C12orf65 is involved in the mitochondrial translation process and has been shown to be associated with a range of phenotypes, including premature optic atrophy, progressive encephalomyosis, peripheral neuropathy and spastic lower limb paralysis. However, the exact role of C12orf65 has not been fully elucidated. Therefore, further research on the gene - phenotype relationship of C12orf65 is necessary.


  1. Heidary G, et al. Optic Atrophy and a Leigh-Like Syndrome Due to Mutations in the C12orf65 Gene: Report of a Novel Mutation and Review of the Literature. Journal of Neuro-ophthalmology, 2014, 34(1): 39-43.
  2. Spiegel R, et al. Delineation of C12orf65-related phenotypes: a genotype–phenotype relationship. European Journal of Human Genetics, 2014, 22: 1019–1025.
  3. Imagawa E, et al. Homozygous p.V116* mutation in C12orf65 results in Leigh syndrome, J Neurol Neurosurg Psychiatry, 2016, 87: 212–216.
  4. Pyle et al. Behr’s Syndrome is Typically Associated with Disturbed Mitochondrial Translation and Mutations in the C12orf65 Gene. J Neuromuscul Dis, 2014, 1(1): 55–63.
  5. Wesolowska M, et al. Adult Onset Leigh Syndrome in the Intensive Care Setting: A Novel Presentation of a C12orf65 Related Mitochondrial Disease. Journal of Neuromuscular Diseases, 2015, 2: 409–419.
  6. Tucci A, et al. Novel C12orf65 mutations in patients with axonal neuropathy and optic atrophy. J Neurol Neurosurg Psychiatry, 2014, 85: 486–492.

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