Table 2.
Genes linked to retinal degeneration in humans, which function in cellular metabolism
| Mutated gene(s) | OMIM | Location | Protein(s) affected | Function of WT protein | Pathogenic consequences of mutation(s) |
|---|---|---|---|---|---|
| RP, autosomal recessive | |||||
| IDH3B | 604526 | 20p13 | NAD(+)-specific isocitrate dehydrogenase 3 beta | Converts isocitrate to α-ketoglutarate in the citric acid cycle | Impaired metabolism/respiration |
| Mitochondrial retinopathies | |||||
| MT-ATP6a | 516060 | mtDNA | Complex V ATPase 6 subunit | ATP synthase | Impaired ATP synthesis |
| MT-TL1b | 590050 | mtDNA | Mitochondria leucine tRNA1 (tRNA-LEU) | tRNA for leucine | Defective respiration |
| MT-THc | 590040 | mtDNA | Mitochondrial histidine tRNA (tRNA-HIS) | tRNA for histidine | Defective respiration |
| MT-TS2d | 590085 | mtDNA | Mitochondrial serine tRNA 2 (tRNA-SER) | tRNA for serine | Defective respiration |
| MT-TPe | 590075 | mtDNA | Mitochondrial proline tRNA (tRNA-PRO) | tRNA for proline | Defective respiration |
| Several deletionsf | 530000 | mtDNA | Several mitochondrial proteins | Respiratory complex (I–V) components and tRNAs | Impaired respiratory complex activity |
| Several missense mutationsg | 535000 | mtDNA | Several mitochondrial proteins (ND1, ND4, ND6) | Complex I, II, and III components | Impaired respiratory complex activity |
| Optic atrophy, autosomal dominant | |||||
| OPA1 | 605290 | 3q29 | OPA1 protein; dynamin-related GTPase | Mitochondrial inner membrane; regulates mitochondrial stability, bioenergetics, and cytochrome c sequestration | Defective respiration, cytochrome c release |
| MFN2 | 608507 | 1p36.22 | Mitofusin 2 | Regulates mitochondrial fusion, morphology, and distribution | Defective fusion, respiration |
| Optic atrophy, autosomal recessive | |||||
| TMEM126A | 11q14.1 | Transmembrane protein 126A | Mitochondrial protein of unknown function | N/A | |
| Optic atrophy, X linked | |||||
| TIMM8A | 300356 | Xq22.1 | Mitochondrial membrane translocase 8 homolog A | Transport of metabolites into mitochondria; import and insertion of proteins into mitochondrial inner membrane | Defective respiration |
| Syndromic/systemic diseases with retinopathy, autosomal recessive | |||||
| PANK2 | 606157 | 20p13 | Pantothenate kinase 2 (mitochondrial/cytoplasmic) | Catalyzes pantothenate phosphorylation | Impaired CoA biosynthesis/respiration |
| OPA3 | 606580 | 19q13.32 | OPA3 protein | May play a role in mitochondrial processes | N/A |
| Other retinopathy, X linked | |||||
| PGK1 | 311800 | Xq21.1 | Phosphoglycerate kinase (cytosolic) | Converts 1,3-diphosphoglycerate to 3-phosphoglycerate (generates 1 ATP molecule) | Defective glycolysis |
Multiple forms of retinal degenerative diseases (RP, mitochondrial retinopathies, optical atrophy, and syndromic diseases) are caused by mutations in genes involved in cellular metabolism and energetics, including components of mitochondrial respiratory chains, mitochondrial structural proteins, enzymes that function in the Krebs cycle, and the glycolysis and several transfer RNAs. For each disease-linked gene, the following information is provided: OMIM access number, genomic location, encoded protein, and function of WT protein, as well as the pathogenic consequences of disease-linked mutations.
aMutations cause RP with developmental and neurological abnormalities (OMIM 551500), Leigh syndrome, and Leber hereditary optic neuropathy (LHON).
bMutations in MTTL1 lead to macular pattern dystrophy with type II diabetes and deafness.
cMutations cause pigmentary retinopathy and sensorineural hearing loss.
dMutations cause RP with progressive sensorineural hearing loss (OMIM 500004).
eMutations cause RP with deafness and neurological abnormalities.
fDeletions found in Kearns-Sayre syndrome, characterized by ophthalmoplegia, pigmentary degeneration of the retina, and cardiomyopathy.
gMissense mutations in several genes leading to LHON.