OPA3 – 3-Methylglutaconic Aciduria Type III

OPA3 encodes two mitochondrial‐targeted transcripts, OPA3A and OPA3B, and loss of OPA3A underlies autosomal recessive 3-Methylglutaconic Aciduria Type III (Costeff syndrome). Clinically, affected individuals present in infancy with bilateral optic atrophy, motor delay, vertical nystagmus, extrapyramidal dysfunction (chorea, dystonia), gait ataxia, dysarthria, and spastic paraparesis, accompanied by elevated urinary 3-methylglutaconic and 3-methylglutaric acids (PMID:20350831).

Genetic evidence for an autosomal recessive inheritance includes: screening of 13 patients identifying two probands with homozygous IVS1-1G>C (PMID:15902555); two siblings compound heterozygous for c.1A>G (p.Met1Val) and c.142+5G>C (PMID:24749080); a consanguineous Afghani family with three siblings homozygous for c.142+2_142+3dup and heterozygous c.313C>G (p.Gln105Glu) (PMID:31928268); and reverse phenotyping in cousins revealing c.32T>A (p.Leu11Gln) (PMID:23700088). Variants span frameshift (c.217dup (p.Glu73fs)), splice-site (c.143-1G>C), missense (c.313C>G (p.Gln105Glu)), and insertion classes, consistent with a loss-of-function mechanism.

Segregation analyses demonstrate co-segregation of pathogenic OPA3 variants in four independent families with at least 4 additional affected relatives, including consanguineous and non-consanguineous pedigrees. No recurrent founder variants have been identified outside the Iraqi Jewish population.

Functional studies localize OPA3 to mitochondria, as demonstrated by GFP‐tagged expression and immunohistochemistry in patient cells, where mutant fibroblasts show fragmented mitochondrial networks and altered cytochrome c oxidase activity (PMID:21613372; PMID:24136862). A murine Opa3 p.Leu122Pro model recapitulates optic nerve degeneration, extrapyramidal dysfunction, cardiomyopathy, and early mortality, mirroring human Type III MGCA (PMID:18222992).

Screening of patients with unexplained 3-methylglutaconic aciduria without classic Costeff features did not identify additional pathogenic OPA3 mutations, indicating specificity of OPA3 variants to the classic clinical phenotype (PMID:15902555).

Together, robust AR segregation in multiple families, diverse loss-of-function variants in >40 probands, and concordant mitochondrial pathology in cellular and animal models support a Strong gene–disease association for OPA3 in 3-Methylglutaconic Aciduria Type III. Key take-home: OPA3 should be included in diagnostic gene panels for early-onset optic atrophy with elevated urinary 3-methylglutaconic acid to enable prompt diagnosis and management.

References

• Molecular Genetics and Metabolism • 2010 • OPA3, mutated in 3-methylglutaconic aciduria type III, encodes two transcripts targeted primarily to mitochondria PMID:20350831
• Journal of Inherited Metabolic Disease • 2005 • OPA3 mutation screening in patients with unexplained 3-methylglutaconic aciduria PMID:15902555
• Molecular Genetics and Metabolism Reports • 2014 • Two novel compound heterozygous mutations in OPA3 in two siblings with OPA3-related 3-methylglutaconic aciduria PMID:24749080
• Ophthalmic Genetics • 2019 • Novel homozygous OPA3 mutation in an Afghani family with 3-methylglutaconic aciduria type III and optic atrophy PMID:31928268
• JAMA Neurology • 2013 • A novel OPA3 mutation revealed by exome sequencing: an example of reverse phenotyping PMID:23700088
• Brain • 2008 • A missense mutation in the murine Opa3 gene models human Costeff syndrome PMID:18222992
• Investigative Ophthalmology & Visual Science • 2011 • Mitochondrial localization and ocular expression of mutant Opa3 in a mouse model of 3-methylglutaconicaciduria type III PMID:21613372
• Journal of Medical Genetics • 2013 • A novel heterozygous OPA3 mutation located in the mitochondrial target sequence results in altered steady-state levels and fragmented mitochondrial network PMID:24136862

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