Alternative titles; symbols
HGNC Approved Gene Symbol: OPA3
SNOMEDCT: 297232009, 719517009;
Cytogenetic location: 19q13.32 Genomic coordinates (GRCh38) : 19:45,527,427-45,584,802 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.32 | 3-methylglutaconic aciduria, type III | 258501 | Autosomal recessive | 3 |
| Optic atrophy 3 with cataract | 165300 | Autosomal dominant | 3 |
OPA3 is an integral protein of the mitochondrial outer membrane that induces mitochondrial fragmentation (Ryu et al., 2010).
By genomic sequencing within the critical mapping interval for 3-methylglutaconic aciduria type III (MGCA3; 258501) on chromosome 19, Anikster et al. (2001) identified a point mutation that segregated with the MGCA3 phenotype in the intronic sequence of a gene, designated OPA3, corresponding to cDNA clone FLJ22187. The OPA3 cDNA encodes a deduced 179-amino acid protein. Northern blot analysis demonstrated a primary transcript of approximately 5.0 kb that was ubiquitously expressed, most prominently in skeletal muscle and kidney. Compared to other parts of the brain, the cerebral cortex, the medulla, the cerebellum, and the frontal lobe had slightly increased expression.
By database analysis and PCR of cultured human fibroblasts, Huizing et al. (2010) cloned 2 splice variants of OPA3. The variants, OPA3A and OPA3B, differ in the splicing of the common exon 1 onto exon 2 or 3, respectively. The deduced OPA3A and OPA3B proteins contain 179 and 180 amino acids, respectively, and are identical for the first 47 N-terminal amino acids, including a putative mitochondrial localization signal. Their C-terminal sequences are also highly homologous and end in putative peroxisomal targeting signals. Real-time quantitative PCR detected tissue-specific expression of both variants in all tissues examined. OPA3A showed highest expression in skeletal muscle and heart, and OPA3B showed highest expression in testis. Fluorescence-tagged OPA3A and OPA3B localized to mitochondria. When mitochondrial localization was blocked, OPA3A, but not OPA3B, localized to peroxisomes. Database analysis revealed conservation of OPA3A from fungi to primates, whereas OPA3B was found only in mammals.
By fractionation analysis, Ryu et al. (2010) showed that OPA3 localized to the outer membrane of mitochondria in HeLa cells. OPA3 was anchored in the outer membrane with its N-terminal region exposed to the mitochondrial intermembrane space and its C-terminal region exposed to the cytosol. Deletion analysis revealed that the N terminus of OPA3 was required for mitochondrial targeting.
Anikster et al. (2001) determined that the OPA3 gene contains 2 exons.
Huizing et al. (2010) determined that the OPA3 gene contains 3 exons and spans 57.3 kb. Intron 1 contains a LINE-1 (L2MC4) transposon. Exons 2 and 3 are highly similar and appear to have originated from a segmental duplication.
By sequence analysis, Anikster et al. (2001) mapped the OPA3 gene to chromosome 19q13.2-q13.3. Huizing et al. (2010) mapped the OPA3 gene to chromosome 19q13.32 by genomic sequence analysis.
Ryu et al. (2010) found that OPA3 overexpression induced mitochondrial fragmentation in HeLa cells, whereas OPA3-knockdown cells had more elongated and tubular mitochondria compared with controls. The effects of OPA3 on mitochondrial morphology were independent of DRP1 (DNM1L; 603850)- and FIS1 (609003)-mediated mitochondrial fission. Instead, overexpression of OPA3 increased sensitivity to apoptotic signals, whereas depletion of OPA3 protected against apoptotic cell death. Deletion analysis revealed that the hydrophobic region of OPA3 was required for mitochondrial fragmentation. OPA3 function appeared to be evolutionarily conserved, as expression of Drosophila OPA3 rescued mitochondrial morphology in OPA3-knockdown HeLa cells.
3-Methylglutaconic Acduria, Type III
In 10 Iraqi Jewish patients from 8 different families with 3-methylglutaconic aciduria type III (MGCA3; 258501), Anikster et al. (2001) identified a homozygous splice site mutation in the OPA3 gene (606580.0001). The mutation was also detected in 8 of 85 healthy ethnically matched controls, yielding a carrier frequency of 1 in 10 and indicating a founder effect. The authors suggested that milder mutations of OPA3 should be sought in patients with optic atrophy with later onset, even in the absence of additional neurologic abnormalities.
In 14 patients with MGCA3, all except one of Iraqi Jewish descent, Yahalom et al. (2014) identified homozygosity for the splice site mutation previously identified by Anikster et al. (2001) in the OPA3 gene.
In a 14-year-old boy, born of first-cousin Kurdish-Turkish parents, with MGCA3, Kleta et al. (2002) identified homozygosity for a deletion in exon 2 of the OPA3 gene (606580.0004).
In 2 cousins (family DYAF09), born to consanguineous Pakistani parents, with MGCA3, Arif et al. (2013) identified a homozygous missense mutation in exon 1 of the OPA3 gene (L11Q; 606580.0005). The mutation, which was identified by genomewide homozygosity mapping and exome sequencing, was confirmed by Sanger sequencing.
In an 18-year-old patient with MGCA3, who was born to nonconsanguineous Indian parents, Ho et al. (2008) identified presumed homozygosity for a nonsense mutation in exon 2 of the OPA3 gene (Q139X; 606580.0006). The father was a carrier for the mutation, but DNA from the mother was not available for testing; Ho et al. (2008) could therefore not exclude the possibility of a deletion of exon 2 on the maternal allele.
Optic Atrophy 3 with Cataract
In affected members of 2 families with autosomal dominant optic atrophy and cataract (OPA3; 165300), Reynier et al. (2004) identified 2 different mutations in the OPA3 gene (G93S, 606580.0002 and Q105E, 606580.0003, respectively).
Anikster et al. (2001) identified an acceptor splice site mutation in the OPA3 gene, IVS1-1G-C, as the cause of 3-methylglutaconic aciduria type III (MGCA3; 258501), or optic atrophy plus syndrome, in several Iraqi Jewish patients. The mutation abolished mRNA expression in the patients' fibroblasts. The mutation was also detected in 8 of 85 healthy ethnically matched controls, yielding a carrier frequency of 1 in 10 and indicating a founder effect.
In 14 patients with MGCA3, all except one of Iraqi Jewish descent, Yahalom et al. (2014) identified homozygosity for the IVS1-1G-C (c.143-1G-C) mutation in the OPA3 gene.
In a 5-year-old girl, born of consanguineous Syrian Jewish parents, with MGCA3, Carmi et al. (2015) identified homozygosity for the c.143-1G-C mutation in the OPA3 gene.
In affected members of a French family with autosomal dominant optic atrophy and cataract (OPA3; 165300) first described by Garcin et al. (1961), Reynier et al. (2004) identified a heterozygous 277G-A transition in exon 2 of the OPA3 gene, resulting in a gly93-to-ser (G93S) substitution.
In affected members of a family with autosomal dominant optic atrophy and cataract (OPA3; 165300), Reynier et al. (2004) identified a heterozygous 313C-G transversion in exon 2 of the OPA3 gene, resulting in a gln105-to-glu (Q105E) substitution.
In a 14-year-old boy, born of first-cousin Kurdish-Turkish parents, with 3-methylglutaconic aciduria type III (MGCA3; 258501), Kleta et al. (2002) identified a homozygous 18-bp deletion in exon 2 of the OPA3 gene, resulting in the deletion of 6 amino acids between codons 108 and 113. As a child, the boy had ataxic gait and 3-methylglutaconic aciduria. Decreased visual acuity with optic atrophy was diagnosed at age 9 years. At age 13, he was physically active with normal intelligence, but had mild ataxic restlessness.
In 2 cousins (family DYAF09) with 3-methylglutaconic aciduria type III (MGCA3; 258501), who were born to consanguineous Pakistani parents, Arif et al. (2013) identified a homozygous c.32T-A transversion (c.32T-A, NM_015136) in exon 1 of the OPA3 gene, resulting in a leu11-to-gln (L11Q) substitution at an evolutionarily conserved residue. The mutation, which was identified by genomewide homozygosity mapping and exome sequencing, was verified by Sanger sequencing and segregated with the disease in the family. The variant was not present in the NHLBI Exome Variant Project database or in 342 Pakistani controls. The mutation affects both OPA3 transcripts (OPA3A and OPA3B) and is located within a potential mitochondrial leader sequence, possibly causing abnormalities in mitochondrial targeting. Both patients also had a homozygous mutation in the TSHZ3 gene (c.941C-G, A314G) that segregated with the disorder in the family. The authors considered the OPA3 mutation to be pathogenic because of the clinical features known to be associated with OPA3 mutations, but could not exclude a possible modifying role for the TSHZ3 mutation. Both patients had optic disc pallor and choreiform and myoclonic movements.
In an 18-year-old patient with 3-methylglutaconic aciduria type III (MGCA3; 258501), who was born to nonconsanguineous Indian parents, Ho et al. (2008) identified a homozygous c.415C-T transition (c.415C-T, NM_025136.2) in exon 2 of the OPA3 gene, resulting in a gln139-to-ter (Q139X) substitution. The early termination codon was predicted to lead to nonsense mediated decay of the OPA3 transcript. The mutation, which was found by Sanger sequencing, was present in heterozygous state in the father, but DNA from the mother was not available for testing. Ho et al. (2008) could not exclude the possibility that the patient had inherited deletion of exon 2 from her mother. The patient had elevated 3-methylglutaconic acid and 3-methylglutaric acid in the urine. She had bilateral optic atrophy and mild ataxia and spasticity.
Anikster, Y., Kleta, R., Shaag, A., Gahl, W. A., Elpeleg, O. Type III 3-methylglutaconic aciduria (optic atrophy plus syndrome, or Costeff optic atrophy syndrome): identification of the OPA3 gene and its founder mutation in Iraqi Jews. Am. J. Hum. Genet. 69: 1218-1224, 2001. [PubMed: 11668429] [Full Text: https://doi.org/10.1086/324651]
Arif, B., Kumar, K. R., Seibler, P., Vulinovic, F., Fatima, A., Winkler, S., Nurnberg, G., Thiele, H., Nurnberg, P., Jamil, A. Z., Bruggemann, A., Abbas, G., Klein, C., Lohmann, K. A novel OPA3 mutation revealed by exome sequencing: an example of reverse phenotyping. JAMA Neurol. 70: 783-787, 2013. [PubMed: 23700088] [Full Text: https://doi.org/10.1001/jamaneurol.2013.1174]
Carmi, N., Lev, D., Leshinsky-Silver, E., Anikster, Y., Blumkin, L., Kivity, S., Lerman-Sagie, T., Zerem, A. Atypical presentation of Costeff syndrome--severe psychomotor involvement and electrical status epilepticus during slow wave sleep. Europ. J. Paediat. Neurol. 19: 733-736, 2015. [PubMed: 26190011] [Full Text: https://doi.org/10.1016/j.ejpn.2015.06.006]
Garcin, R., Raverdy, P., Delthil, S., Man, H. X., Chimenes, H. Sur une affection heredo-familiale associant cataracte, atrophie optique, signes extra-pyramidaux et certains stigmates de la maladie de Friedreich. (Sa position nosologique par rapport au syndrome de Behr, au syndrome de Marinesco-Sjogren et a la maladie de Friedreich avec signes oculaires.). Rev. Neurol. 104: 373-379, 1961. [PubMed: 13703570]
Ho, G., Walter, J. H., Christodoulou, J. Costeff optic atrophy syndrome: new clinical case and novel molecular findings. J. Inherit. Metab. Dis. 31 (Suppl. 2): S419-S423, 2008. [PubMed: 18985435] [Full Text: https://doi.org/10.1007/s10545-008-0981-z]
Huizing, M., Dorward, H., Ly, L., Klootwijk, E., Kleta, R., Skovby, F., Pei, W., Feldman, B., Gahl, W. A., Anikster, Y. OPA3, mutated in 3-methylglutaconic aciduria type III, encodes two transcripts targeted primarily to mitochondria. Molec. Genet. Metab. 100: 149-154, 2010. [PubMed: 20350831] [Full Text: https://doi.org/10.1016/j.ymgme.2010.03.005]
Kleta, R., Skovby, F., Christensen, E., Rosenberg, T., Gahl, W. A., Anikster, Y. 3-Methylglutaconic aciduria type III in a non-Iraqi-Jewish kindred: clinical and molecular findings. Molec. Genet. Metab. 76: 201-206, 2002. [PubMed: 12126933] [Full Text: https://doi.org/10.1016/s1096-7192(02)00047-1]
Reynier, P., Amati-Bonneau, P., Verny, C., Olichon, A., Simard, G., Guichet, A., Bonnemains, C., Malecaze, F., Malinge, M. C., Pelletier, J. B., Calvas, P., Dollfus, H., Belenguer, P., Malthiery, Y., Lenaers, G., Bonneau, D. OPA3 gene mutations responsible for autosomal dominant optic atrophy and cataract. J. Med. Genet. 41: e110, 2004. Note: Electronic Article. [PubMed: 15342707] [Full Text: https://doi.org/10.1136/jmg.2003.016576]
Ryu, S. W., Jeong, H. J., Choi, M., Karbowski, M., Choi, C. Optic atrophy 3 as a protein of the mitochondrial outer membrane induces mitochondrial fragmentation. Cell. Molec. Life Sci. 67: 2839-2850, 2010. [PubMed: 20372962] [Full Text: https://doi.org/10.1007/s00018-010-0365-z]
Yahalom, G., Anikster, Y., Huna-Baron, R., Hoffmann, C., Blumkin, L., Lev, D., Tsabari, R., Nitsan, Z., Lerman, S. F., Ben-Zeev, B., Pode-Shakked, B., Sofer, S., Schweiger, A., Lerman-Sagie, T., Hassin-Baer, S. Costeff syndrome: clinical features and natural history. J. Neurol. 261: 2275-2282, 2014. [PubMed: 25201222] [Full Text: https://doi.org/10.1007/s00415-014-7481-x]