| *605290 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| OPA1 GENE; OPA1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| KIAA0567 DYNAMIN-LIKE 120-KD PROTEIN, MITOCHONDRIAL | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: OPA1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cytogenetic location: 3q29 Genomic coordinates (GRCh37): 3:193,310,932 - 193,415,599 (from NCBI) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Phenotype Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| TEXT | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The OPA1 gene encodes a protein that localizes to the inner mitochondrial membrane and regulates several important cellular processes including stability of the mitochondrial network, mitochondrial bioenergetic output, and sequestration of proapoptotic cytochrome c oxidase molecules within the mitochondrial cristae spaces (summary by Yu-Wai-Man et al., 2010). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cloning | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1998) cloned OPA1, which they designated KIAA0567. The deduced protein contained 978 amino acids. RT-PCR detected highest OPA1 expression in heart and kidney, with low expression in all other tissues examined. In the fission yeast S. pombe, Pelloquin et al. (1998, 1999) identified a dynamin-related protein, Msp1, essential for the maintenance of mitochondrial DNA, as is true for Mgm1p, its ortholog in S. cerevisiae (Jones and Fangman, 1992). Both proteins have a GTPase and a central dynamin domain conserved among all dynamins and a highly basic N-terminal domain required for mitochondrial localization. Delettre et al. (2000) searched for a human Msp1/Mgm1p homolog in nucleotide databases and identified the KIAA0567 cDNA previously cloned by Nagase et al. (1998). The 960-amino acid protein shared 19% and 17% identity to Msp1 and Mgm1p, respectively. Delettre et al. (2000) then retrieved the sequence of the gene, which they referred to as OPA1, in 2 overlapping clones from the Whitehead Institute server. Labeling studies indicated that Opa1 is a component of the mitochondrial network. Mitochondrial localization of OPA1 was also consistent with a ubiquitous expression of its transcripts in all tissues examined by Northern blot. Alexander et al. (2000) established a PAC contig covering the entire optic atrophy-1 (165000) candidate region of approximately 1 Mb. By a sequence skimming approach, they independently identified the the OPA1 gene, encoding a polypeptide with homology to dynamin-related GTPases. By RT-PCR of human RNA, Delettre et al. (2001) cloned 8 OPA1 variants resulting from alternative splicing of exons 4, 4b, and 5b. All 8 OPA1 isoforms contain an N-terminal mitochondrial leader sequence, a central coiled-coil region, a GTPase domain, a dynamin central region, and a C-terminal coiled-coil region. Exons 4b and 5b encode 18- and 37-amino acid sequences, respectively. The sequence encoded by exon 5b was predicted to form a coiled-coil. RT-PCR detected variable expression of all 8 OPA1 variants in the 11 tissues tested. In retina, heart, skeletal muscle, lung, ovary, and fetal brain, variants 3/4/5/6 and 3/5/5b/6, in which the numbers indicate the exons present from exon 3 to exon 6, showed highest expression. In kidney, liver, and colon, variant 3/4/5/5b/6 showed highest expression. Except in skeletal muscle, variants 3/4b/5/5b/6 and 3/4/4b/5/6 showed low expression. Variants 3/5/6 and 3/4b/5/6 were weakly expressed in all tissues. Olichon et al. (2007) further characterized the 8 OPA1 splice variants. They reported that all 8 OPA1 isoforms have a transmembrane domain immediately following the N-terminal mitochondrial targeting signal. The isoforms differ only in the presence or absence of domains 4, 4b, and 5b, which are encoded by exons 4, 4b, and 5b, respectively, within the region between the transmembrane domain and the central coiled-coil region. Olichon et al. (2007) also presented evidence suggesting that short forms of the OPA1 isoforms are produced by proteolytic processing. Exon-specific qualitative PCR revealed tissue-specific expression of OPA1 variants, with variant 3/4/4b/6 predominating in brain, variant 3/4/5/6 predominating in heart, and variant 3/4/5b/6 predominating in liver, kidney, and thymus. Phylogenetic analysis revealed that exon 4 is conserved throughout evolution, whereas exons 4b and 5b are vertebrate specific. Elachouri et al. (2011) stated that the common C-terminal domain found in all OPA1 isoforms contains a GTPase domain and a GTPase effector domain (GED). They also reported that exon 4b encodes a second transmembrane domain. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Structure | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alexander et al. (2000) stated that the OPA1 gene comprises 28 coding exons and spans more than 40 kb of genomic sequence. Delettre et al. (2001) reported that the OPA1 gene contains 31 exons, including the alternatively spliced exons 4, 4b, and 5b. The last exon in noncoding. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| By fluorescence in situ hybridization, Delettre et al. (2000) mapped the OPA1 gene to chromosome 3q28-q29, the region to which the locus for optic atrophy-1 had been mapped. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Function | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Olichon et al. (2003) determined that the downregulation of OPA1 in HeLa cells with expression of specific small interfering RNA (siRNA) leads to fragmentation of the mitochondrial network, dissipation of the mitochondrial membrane potential, and disorganization of the cristae. These events were followed by cytochrome c (123970) release and caspase (see 600636)-dependent apoptotic nuclear events. In a human ovarian carcinoma cell line, siRNA-induced apoptosis was inhibited by BCL2 (151430) overexpression. Olichon et al. (2003) concluded that OPA1 is a major organizer of the mitochondrial inner membrane and is required for the maintenance of cristae integrity. As the loss of OPA1 committed cells to apoptosis without any other stimulus, Olichon et al. (2003) proposed that OPA1 is involved in the sequestration of cytochrome c, and that OPA1 may be a target for mitochondrial apoptotic effectors. They also proposed that abnormal apoptosis is a likely process leading to the retinal ganglion cell degeneration in autosomal dominant optic atrophy (165500) patients. Meeusen et al. (2004) captured mitochondrial fusion in vitro in transgenic experiments using yeast mitochondria. They found that mitochondrial outer and inner membrane fusion events were separable and mechanistically distinct, but both required GTP hydrolysis. Homotypic trans interactions of the ancient outer transmembrane GTPase, Fzo1 (see MFN1; 608506), were required to promote the fusion of mitochondrial outer membranes, whereas electrical potential was also required for fusion of inner membranes. Meeusen et al. (2004) found that outer membrane fusion required GTP and trans Fzo interactions on opposing mitochondria, suggesting that GTP promotes outer membrane fusion by means of Fzo1. The only known fusion protein associated with the inner membrane is the dynamin-related GTPase protein (DRP) Mgm1, of which OPA1 is the human ortholog. Cipolat et al. (2004) determined that both the GTPase domain and the C-terminal coiled-coil domain of mouse Opa1 were required to promote the formation of branched network of elongated mitochondria in mouse embryonic fibroblasts. Stable reduction of Opa1 levels by RNA interference resulted in small, fragmented, and scattered mitochondria. The level of Opa1 did not affect mitochondrial docking, but it correlated with the extent of mitochondrial fusion. Using RNA interference against mouse Opa1 in Mfn1-null mouse embryonic fibroblasts, Cipolat et al. (2004) demonstrated an interdependence between Opa1 and Mfn1 in promoting mitochondrial elongation. Using mouse embryonic fibroblasts, Frezza et al. (2006) showed that Opa1 regulated apoptosis by controlling cristae remodeling and cytochrome c redistribution. This function correlated with Opa1 oligomerization and was dependent on cleavage of Opa1 by Parl (607858). Frezza et al. (2006) concluded that oligomerization of OPA1 regulates apoptosis by maintaining the tightness of cristae junctions. Olichon et al. (2007) found that silencing of exon 4-containing OPA1 variants in HeLa cells led to the disappearance of the 4 most abundant OPA1 isoforms, whereas silencing of variants containing exon 4b or 5b had little effect. Overexpression and knockdown studies showed that OPA1 isoforms containing domain 4, but not those containing domain 4b or 5b, were involved in maintenance of the mitochondrial membrane potential and fusion of the mitochondrial network. Conversely, knockdown of variants containing exon 4b or 5b led to apoptosis in the absence of mitochondrial morphologic changes or dissipation of the membrane potential. Using conditional gene targeting, Merkwirth et al. (2008) restricted expression of mouse prohibitin-2 (PHB2; 610704) to mitochondria and identified processing of Opa1 as the central cellular process controlled by prohibitins. Deletion of Phb2 led to selective loss of long isoforms of Opa1, resulting in aberrant cristae morphogenesis, impaired cellular proliferation, and resistance to apoptosis. Expression of a long Opa1 isoform in Phb2-deficient cells suppressed these defects, identifying impaired Opa1 processing as the primary cellular defect in the absence of prohibitins. Merkwirth et al. (2008) concluded that prohibitins are essential for Opa1-dependent formation of mitochondrial cristae. By immunostaining, Amati-Bonneau et al. (2005) found that the OPA1 protein was ubiquitously distributed in sensory and neural cochlear cells of the guinea pig. Mitochondrial nucleoids are autonomous replication units that contain 6 to 10 copies of mitochondrial DNA (mtDNA) and associated proteins. Elachouri et al. (2011) found that a 10-kD peptide generated by proteolytic processing of an OPA1 isoform containing domain 4b localized to mitochondrial nucleoids. This peptide, designated NT-OPA1-exon4b, was generated by proteolytic removal of the mitochondrial localization signal followed by YME1L (607472)-mediated cleavage within the exon 5-encoded domain, which released the C-terminal GTPase domain and GED. Fractionation and biochemical analysis showed that NT-OPA1-exon4b bound to the inner mitochondrial membrane, and chromatin immunoprecipitation studies showed that it also bound to nucleoid DNA. Knockdown of exon 4b-containing OPA1 variants inhibited mtDNA replication and altered the size and distribution of nucleoids. Elachouri et al. (2011) concluded that NT-OPA1-exon4b influences replication of mtDNA. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 6 unrelated families with dominant optic atrophy, Delettre et al. (2000) identified 4 different mutations in heterozygous state. One of the mutations was found in 3 families who were apparently unrelated but who all originated from the northern French provinces and Belgium. Alexander et al. (2000) identified mutations in the OPA1 gene in 7 independent families. Pesch et al. (2001) identified mutations in the OPA1 gene in 25 of 78 independent autosomal dominant optic atrophy families screened. Most missense mutations clustered within the putative GTPase domain, and there was a preponderance of mutations that resulted in premature translation termination. Clinical examination revealed considerable variability in disease expression among patients carrying OPA1 mutations and no strict correlation with either the position or the type of mutation. Their observations supported the notion that haploinsufficiency may represent a major pathomechanism for dominant optic atrophy. In addition, the authors identified a dominant optic atrophy patient who was a compound heterozygote for 2 OPA1 missense mutations. The patient was much more severely affected than her simple heterozygotic parents and sibs, implying that these OPA1 alleles appear to behave semidominantly rather than purely dominantly. Toomes et al. (2001) found mutations in OPA1 in 20 of 35 dominant optic atrophy patients screened. The predominance of null mutations further suggests that the mechanism underlying optic atrophy is haploinsufficiency. To investigate whether LHON could be caused by mutations in OPA1, the authors also screened a panel of 28 LHON patients who tested negatively for the 3 major LHON mutations. No mutations were identified in any LHON patients, indicating that dominant optic atrophy and LHON are genetically distinct. Delettre et al. (2001) screened a cohort of 19 unrelated patients with dominant optic atrophy by direct sequencing of the 30 OPA1 exons (including exons 4b and 5b) and found 15 different mutations, 8 of which were novel, in 17 (89%) patients. Most of the mutations were truncating (65%) and located in exons 8 to 28, but a number of them were amino acid changed located predominantly in the GTPase domain in exons 8 to 15. Delettre et al. (2001) hypothesized that at least 2 modifications of OPA1 may lead to dominant optic atrophy: alteration in GTPase activity and loss of the last 7 C-terminal amino acids that putatively interact with other proteins. Shimizu et al. (2003), Li et al. (2005), and Amati-Bonneau et al. (2005) identified the same heterozygous mutation in the OPA1 gene (R445H; 605290.0011) in several unrelated patients with optic atrophy, deafness, and neuromuscular complications (125250), suggesting that this mutation is specifically associated with the phenotype. Normal tension glaucoma (NTG; 606657) is an important subtype of primary open angle glaucoma, in which the intraocular pressure (IOP) is consistently within the statistically normal population range. Aung et al. (2002) screened 83 well-characterized NTG patients for mutations in the OPA1 gene by heteroduplex analysis and bidirectional sequencing. In this and a second cohort of 80 NTG patients, they found that a single nucleotide polymorphism (SNP) on intervening sequence (IVS) 8, IVS8+4C/T, was strongly associated with the occurrence of NTG. A second SNP, IVS8+32T/C, appeared to be associated with disease in the first cohort, but this finding could not be replicated in a second cohort. In the combined cohort, the compound at-risk genotype IVS8+4C/T,+32T/C (605290.0010) was strongly associated with the occurrence of NTG (P = 0.00001 after correcting for testing of 4 genotypes). These results indicated that polymorphisms in the OPA1 gene are associated with NTG and may be a marker for the disease. Schimpf et al. (2006) identified and characterized 4 intronic and 3 exonic OPA1 gene mutations that caused a variety of splicing defects and transcript processing defects, including activation of cryptic splice sites. Schimpf et al. (2008) analyzed OPA1 transcripts from 37 different OPA1 mutations, including 22 novel mutations, from 42 OPA1 patients or families. These included 11 missense, 3 nonsense, and 15 splice site mutations, and 7 deletions and/or insertions. All missense mutations were located in the GTPase domain: 8 resulted in an amino acid exchange, and 3 were in the last or penultimate nucleotide of an exon, resulting in a leaky splice defect. Eleven splice site mutations resulted in complete skipping of an adjacent exon, whereas 4 resulted in activation of a cryptic splice site. Using pyrosequencing technology, Schimpf et al. (2008) demonstrated that nonsense or frameshift mutations were associated with a 20 to 50% reduced level of mutant mRNA transcripts in corresponding patient samples, although these levels varied between family members with the same mutation and between blood and lymphoblastoid cells from the same individual. RNA transcripts from lymphoblastoid cells were less stable compared to blood samples. These findings suggested that nonsense-mediated decay occurs to a different degree depending on specific mutation type or location, as well as cell or tissue type. Schimpf et al. (2008) concluded that haploinsufficiency of OPA1 is the pathomechanism in this disorder. Using multiplex ligation probe amplification (MLPA), Fuhrmann et al. (2009) identified heterozygous deletions of 1 or more exons in the OPA1 gene in 5 of 42 OPA1 probands who did not have point mutations by previous screening techniques. Three additional probands had a heterozygous in-frame duplication of exons 7 to 9. Overall, the results were consistent with haploinsufficiency as a disease mechanism rather than gain of function. Fuhrmann et al. (2009) estimated that OPA1 genomic rearrangements have a prevalence of 12.9% in patients with autosomal dominant optic atrophy. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genotype/Phenotype Correlations | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Among 104 patients from 45 families with 33 different OPA1 mutations, Yu-Wai-Man et al. (2010) found that multisystem neurologic disease involving optic atrophy, deafness, and neuromuscular complications (125250) was associated with all types of mutations; however, there was an increased risk with missense mutations (odds ratio (OR) of 3.06, p = 0.0027) and with mutations located within the GTPase region (OR of 2.29, p = 0.0271). Skeletal muscle biopsies from those with extraocular neurologic features showed higher levels of cytochrome c oxidase-deficient fibres and mitochondrial DNA deletions compared to those with pure optic neuropathy, suggesting a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Animal Model | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Davies et al. (2007) generated mutant mice carrying an ethylnitrosourea (ENU)-induced Q285X mutation in the Opa1 gene, resulting in a truncated protein. Western analysis showed that the mutation resulted in approximately 50% reduction in Opa1 protein in retina and all tissues. The homozygous mutation was embryonic lethal by 13.5 days postcoitum. Fibroblasts from adult heterozygotes showed an increase in mitochondrial fission and fragmentation. In addition, electron microscopy revealed the slow onset of optic nerve degeneration; reduced visual function in heterozygotes was demonstrated by optokinetic drum testing and the circadian running wheel. Davies et al. (2007) concluded that the OPA1 GTPase contains crucial information required for the survival of retinal ganglion cells and that OPA1 is essential for early embryonic survival. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Table View | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0001 OPTIC ATROPHY 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| OPA1, GLY300GLU [dbSNP:rs28939082] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In affected members of one family with autosomal dominant optic atrophy (165500), Delettre et al. (2000) found an 899G-A transition in exon 9 of the OPA1 gene that changed glycine to glutamic acid at codon 300. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0002 OPTIC ATROPHY 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| OPA1, IVS9AS, G-A, -1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In affected members of a family with autosomal dominant optic atrophy (165500), Delettre et al. (2000) found a G-to-A transition in the last nucleotide of intron 9 of the OPA1 gene that abolished the acceptor splice site. This mutation results in either skipping of exon 10 with no frameshift in the following exon 11, or a frameshift with a premature stop at the first codon of exon 10 (329) if the newly ectopic acceptor splice site 1 bp downstream of the original is functional. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0003 OPTIC ATROPHY 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| OPA1, 4-BP DEL, 2708TTAG [dbSNP:rs80356530] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 3 families, Delettre et al. (2000) found that members with autosomal dominant optic atrophy (165500) had a 4-bp deletion in exon 27 of the OPA1 gene, 2708delTTAG, that caused 2 amino acid substitutions (val903 to gly, arg904 to asp) and a premature stop at codon 905. This mutation was present in an asymptomatic carrier in one family but was fully penetrant in the other 2 families. This penetrance was expected since minimally affected patients and asymptomatic carriers (with no detectable optic atrophy on fundus examination) had been described. The 3 families were apparently unrelated, but all originated from the northern French provinces and Belgium. Founder effect had been demonstrated by haplotype studies in the British Isles (Votruba et al., 1998; Johnston et al., 1999). Toomes et al. (2001) haplotyped 8 unrelated individuals with the 2708delTTAG mutation and concluded that this may be a mutation hotspot and not an ancient mutation, thus excluding a major founder effect at the OPA1 locus. A recalculation of the penetrance of this disorder within 2 of 8 families indicated figures as low as 43 and 62% associated with the 2708delTTAG mutation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0004 OPTIC ATROPHY 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| OPA1, 4-BP DEL, 2823AGTT | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In affected members of a family with autosomal dominant optic atrophy (165500), Delettre et al. (2000) found a 4-bp deletion in exon 28 of the OPA1 gene (2823delAGTT) that caused a delayed stop, downstream of the original one, resulting in the replacement of the last 19 amino acids of the protein with 24 novel amino acids at the carboxy terminus. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0005 OPTIC ATROPHY 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| OPA1, ARG290GLN [dbSNP:rs121908375] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a family from Cuba, Alexander et al. (2000) demonstrated that members with autosomal dominant optic atrophy (165500) had a G-to-A transition of nucleotide 869 in exon 8 of the OPA1 gene, predicting an arg290-to-gln amino acid change. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0006 OPTIC ATROPHY 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| OPA1, ARG366TER [dbSNP:rs104893752] [dbSNP:rs104893753] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a German family, Alexander et al. (2000) found that individuals with autosomal dominant optic atrophy (165500) had a C-to-T transition of nucleotide 1096 in exon 11 of the OPA1 gene, predicted to cause an arg366-to-ter change in the protein. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0007 OPTIC ATROPHY 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| OPA1, 3-BP DEL, 1296CAT | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In affected members of a U.K. family with autosomal dominant optic atrophy (165500), Alexander et al. (2000) found a 3-bp deletion, del1296CAT, in exon 13 of the OPA1 gene resulting in deletion of the amino acid isoleucine-432. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0008 OPTIC ATROPHY 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| OPA1, 1-BP DEL, 1354G | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a second German family with autosomal dominant optic atrophy (165500), Alexander et al. (2000) found that affected members had a 1-bp deletion in the OPA1 gene, 1354delG, causing a frameshift followed by 14 novel amino acids before termination. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0009 OPTIC ATROPHY 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| OPA1, 1-BP DEL, 2826T [dbSNP:rs80356531] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The prevalence of Kjer type optic atrophy (165500) is reported to be highest in Denmark of any geographic area, suggesting a founder effect. In a sample of 33 apparently unrelated Danish families, Thiselton et al. (2001) screened DNA from affected members for OPA1 gene mutations by heteroduplex analysis and direct sequencing. In 14 pedigrees, a novel identical mutation in exon 28, 2826delT, was associated with dominant optic atrophy and led to a frameshift and an abnormal C terminus of the OPA1 protein. Haplotype analysis revealed a common haplotype shared by all 14 patients; this haplotype was markedly overrepresented compared with ethnically matched controls. Statistical analysis confirmed significant linkage disequilibrium with dominant optic atrophy over approximately 600 kb encompassing the disease mutation. The authors concluded that a founder mutation is responsible for approximately 42% of the families studied and suggested that presymptomatic screening for the 2826delT mutation may facilitate diagnosis and genetic counseling. The disorder is characterized by an insidious onset of visual impairment in early childhood with moderate to severe loss of visual acuity, temporal optic disc pallor, color vision deficits, and centrocecal scotoma of variable density. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0010 GLAUCOMA, NORMAL TENSION, SUSCEPTIBILITY TO | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| OPA1, IVS8, C-T, +4 AND IVS8, T-C, +32 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Aung et al. (2002) found a strong association of normal tension glaucoma (NTG; 606657) with the T allele at the IVS8+4C/T SNP in combination with the C allele at the IVS8+32T/C SNP of the OPA1 gene in Caucasians. In a second publication, Aung et al. (2002) found no significant association of this double polymorphism of intron 8 of the OPA1 gene in high-tension primary open angle glaucoma, suggesting a fundamental difference between the 2 forms. Mabuchi et al. (2007) found a significant association of NTG with the IVS8+32C-T SNP, but not with the IVS8+4C-T SNP, in Japanese. In 137 patients with primary open angle glaucoma (POAG), including 67 with high tension glaucoma (HTG) and 70 with NTG, and 75 controls from the northeast of England, Yu-Wai-Man et al. (2010) found significant association between the T allele at IVS8+4C-T and the risk of developing NTG (odds ratio, 2.04; p = 0.004) but not HTG. Logistic regression analysis confirmed a strong association between the CT/TT compound genotype at IVS8+4 and IVS8+32 with NTG (odds ratio, 29.75; p = 0.001). Yu-Wai-Man et al. (2010) concluded that the CT/TT compound genotype in intron 8 of the OPA1 gene is a strong genetic risk determinant for NTG but not HTG. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0011 OPTIC ATROPHY WITH OR WITHOUT DEAFNESS, OPHTHALMOPLEGIA, MYOPATHY, ATAXIA, AND NEUROPATHY | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| OPA1, ARG445HIS [dbSNP:rs80356529] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a Japanese patient with optic atrophy and moderate sensorineural deafness (125250), Shimizu et al. (2003) identified a heterozygous G-to-A transition in the second nucleotide at codon 445 in the OPA1 gene, resulting in an arg445-to-his (R445H) substitution in the GTPase domain. Payne et al. (2004) found this mutation in a large Utah family and an unrelated Belgian family, previously described by Treft et al. (1984) and Meire et al. (1985), respectively. Both families had optic atrophy, deafness, and ophthalmoplegia. The authors hypothesized that, although OPA1 is a nuclear gene, the localization of its gene product to mitochondria suggests that mitochondrial dysfunction might be the final common pathway for many forms of syndromic and nonsyndromic optic atrophy, hearing loss, and external ophthalmoplegia. In a third family with optic atrophy and hearing loss, unrelated to the Utah or Belgian families, Li et al. (2005) identified the R445H mutation. Li et al. (2005) noted that affected members of this family did not have extraocular motility abnormalities or ptosis, thus illustrating the intra- and interfamilial phenotype variability associated with this mutation. Amati-Bonneau et al. (2005) identified the R445H mutation in 5 unrelated patients from 4 families with optic atrophy and deafness, thus confirming that this mutation is specifically associated with hearing loss. One of the patients had been previously reported by Amati-Bonneau et al. (2003). In the Spanish mother and daughter previously reported by Amati-Bonneau et al. (2005), Amati-Bonneau et al. (2008) noted that the mother had additional features including myopathy, neuropathy, and progressive external ophthalmoplegia. Stewart et al. (2008) identified the R445H mutation in 2 probands with optic atrophy and myopathy associated with mitochondrial DNA deletions. One proband also had deafness. The other proband did not have hearing loss, but 3 affected family members had hearing loss. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0012 OPTIC ATROPHY 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| OPTIC ATROPHY WITH OR WITHOUT DEAFNESS, OPHTHALMOPLEGIA, MYOPATHY, ATAXIA, AND NEUROPATHY, INCLUDED | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| OPA1, 2-BP DEL, 2848GA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a Chinese family in which 9 members had autosomal dominant optic atrophy (165500), accompanied in some by high frequency hearing loss (125250) and/or myopia, Chen et al. (2007) identified a 2-bp deletion in exon 28 of the OPA1 gene (2848_2849delGA), which resulted in a premature stop at codon 953 and a loss of the last 11 amino acids of the protein, in all affected members. The mutation was absent in a family member with myopia alone as well as in all unaffected family members and 100 normal controls. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0013 OPTIC ATROPHY WITH OR WITHOUT DEAFNESS, OPHTHALMOPLEGIA, MYOPATHY, ATAXIA, AND NEUROPATHY | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| OPA1, TYR582CYS [dbSNP:rs121908376] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a patient with progressive external ophthalmoplegia, visual loss, hearing loss, and mild myopathy and ataxia (125250), Ferraris et al. (2008) identified a heterozygous 1741A-G transition in the OPA1 gene, resulting in a tyr582-to-cys (Y582C) substitution. The patient was also found to carry a gly416-to-ala (G416A) variant in the POLG2 gene (604983), but in vitro functional studies showed no functional deficits of the POLG2 variant. Ferraris et al. (2008) concluded that the OPA1 mutation was responsible for the phenotype. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0014 OPTIC ATROPHY WITH OR WITHOUT DEAFNESS, OPHTHALMOPLEGIA, MYOPATHY, ATAXIA, AND NEUROPATHY | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| OPA1, ILE432VAL | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a brother and sister with optic atrophy, progressive external ophthalmoplegia, myopathy, ataxia, but no hearing loss (125250), Stewart et al. (2008) identified heterozygosity for a 1294A-G transition in the OPA1 gene, resulting in an ile432-to-val (I432V) substitution in the GTPase domain. The mutation was not detected in 344 control chromosomes. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0015 OPTIC ATROPHY WITH OR WITHOUT DEAFNESS, OPHTHALMOPLEGIA, MYOPATHY, ATAXIA, AND NEUROPATHY | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| OPA1, SER545ARG | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 7 affected members of a 3-generation family with optic atrophy, ataxia, and progressive external ophthalmoplegia (125250), Hudson et al. (2008) identified heterozygosity for a 1635C-G transversion in exon 17 of the OPA1 gene, resulting in a ser545-to-arg (S545R) substitution in the GTPase domain. Three patients had deafness with onset in the third or fourth decade, and 3 patients had neuropathy and myopathy. In 3 affected members of an Austrian family with optic atrophy, deafness, progressive external ophthalmoplegia, ataxia, and neuropathy (125250), Yu-Wai-Man et al. (2010) identified a heterozygous S545R mutation, which they noted was in the dynamin domain of the protein. Two patients in their thirties had deafness, whereas an older family member in her sixties did not have deafness. The authors also identified the S545R mutation in a 30-year-old French man with optic atrophy, deafness, ataxia, myopathy, and neuropathy. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0016 OPTIC ATROPHY WITH OR WITHOUT DEAFNESS, OPHTHALMOPLEGIA, MYOPATHY, ATAXIA, AND NEUROPATHY | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| OPA1, GLY439VAL | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In an Italian man with optic atrophy, deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy (125250), Amati-Bonneau et al. (2008) identified a heterozygous 1316G-T transversion in exon 14 of the OPA1 gene, resulting in a gly439-to-val (G439V) substitution in the GTPase domain. His 7-year-old daughter also carried the G439V mutation and had optic atrophy and deafness. The mutation was not identified in 460 control chromosomes. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| REFERENCES | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||