ABSTRACT
OPA1 is a dynamin-related GTPase that controls mitochondrial dynamics, cristae integrity, energetics and mtDNA maintenance. The exceptional complexity of this protein is determined by the presence, in humans, of eight different isoforms that, in turn, are proteolytically cleaved into combinations of membrane-anchored long forms and soluble short forms. Recent advances highlight how each OPA1 isoform is able to fulfill "essential" mitochondrial functions, whereas only some variants carry out "specialized" features. Long forms determine fusion, long or short forms alone build cristae, whereas long and short forms together tune mitochondrial morphology. These findings offer novel challenging therapeutic potential to gene therapy.
Subject(s)
Alternative Splicing , GTP Phosphohydrolases/genetics , Mitochondria/enzymology , Mitochondrial Membranes/enzymology , Optic Atrophy, Autosomal Dominant/therapy , Animals , DNA, Mitochondrial/chemistry , DNA, Mitochondrial/genetics , DNA, Mitochondrial/metabolism , GTP Phosphohydrolases/chemistry , GTP Phosphohydrolases/metabolism , GTP Phosphohydrolases/therapeutic use , Gene Expression , Genetic Therapy/methods , Humans , Isoenzymes/chemistry , Isoenzymes/genetics , Isoenzymes/metabolism , Isoenzymes/therapeutic use , Mitochondria/ultrastructure , Mitochondrial Dynamics/genetics , Mitochondrial Membranes/ultrastructure , Optic Atrophy, Autosomal Dominant/enzymology , Optic Atrophy, Autosomal Dominant/genetics , Optic Atrophy, Autosomal Dominant/pathology , Oxidative PhosphorylationABSTRACT
PURPOSE: To report a novel mutation of the OPA1 gene in a Japanese patient with optic atrophy and to describe the clinical features of the patient. DESIGN: Observational case report. METHODS: Genomic DNA was extracted from leukocytes of four unrelated Japanese patients with optic atrophy. All the exons and splice sites of the OPA1 gene were amplified by polymerase chain reaction and directly sequenced. RESULTS: One patient with optic atrophy had a heterozygous Arg445His mutation in the OPA1 gene. The Arg445His mutation was detected neither in 110 control subjects nor in the patient's healthy family members. CONCLUSIONS: A novel mutation of the OPA1 gene, similar to those reported in Western countries, was detected in a Japanese patient with optic atrophy. Mutations of the OPA1 gene may contribute to the development of optic nerve atrophy in Japanese cases of optic atrophy.
Subject(s)
GTP Phosphohydrolases/genetics , Optic Atrophy, Autosomal Dominant/enzymology , Optic Atrophy, Autosomal Dominant/genetics , Point Mutation , Adolescent , Adult , Child , DNA/analysis , Humans , Japan/epidemiology , Male , Optic Atrophy, Autosomal Dominant/ethnology , Pedigree , Polymerase Chain ReactionABSTRACT
The OPA1 gene, encoding a dynamin-related GTPase that plays a role in mitochondrial biogenesis, is implicated in most cases of autosomal dominant optic atrophy (ADOA). Sixty-nine pathogenic OPA1 mutations have been reported so far. Most of these are truncating mutations located in the GTPase domain coding region (exons 8-16) and at the 3'-end (exons 27-28). We screened 44 patients with typical ADOA using PCR-sequencing. We also tested 20 sporadic cases of bilateral optic atrophy compatible with ADOA. Of the 18 OPA1 mutations found, 14 have never been previously reported. The novel mutations include one nonsense mutation, 3 missense mutations, 6 deletions, one insertion and 3 exon-skipping mutations. Two of these are de novo mutations, which were found in 2 patients with sporadic optic atrophy. The recurrent c.2708_2711delTTAG mutation was found in 2 patients with a severe congenital presentation of the disease. These results suggest that screening for OPA1 gene mutations may be useful for patients with optic atrophy who have no affected relatives, or when the presentation of the disease is atypical as in the case of early onset optic atrophy.
