Chronic Progressive External Ophthalmoplegia Is Associated with a Novel Mutation in the Mitochondrial tRNAAsn Gene

Abstract

Chronic progressive extern al ophthalmoplegia (CPEO) is caused by a decreased oxidative phosphorylation (OXPHOS) activity due to large-scale deletions of the mitochondrial genome in 50 % of the patients. The deletions encompass structural OXPHOS genes as weil as tRNA genes, required for their expression so that the pathogenesis could be due to the deleted OXPHOS subunits or to an impaired mitochondrial translation. We have analyzed the mitochondrial genome of a patient presenting with CPEO for single base substitutions and discovered a novel heteroplasmic mutation in the tRNAA,n gene at position 5692 that converts a highly conserved adenine into a guanine. This mutation is unique because it is located at the transition of the anticodon loop to the anticodon stern and it leads to an additional base pair, thus reducing the number of loop-forming nucleotides from seven to five. Our findings suggest that CPEO can be caused by a single base substition in a mitochondrial tRNA gene so that the mitochondrial protein synthesis becomes the rate limiting step in OXPHOS fidelity.

A novel mutation in the mitochondrial tRNAAla gene (m.5636T>C) in a patient with progressive external ophthalmoplegia

“…Maternally inherited cases of PEO have also been reported, associated with mutations in different genes encoded by mtDNA, most frequently mt-tRNA Ile , mt tRNA Leu(CUN) and mt-tRNA Leu(UUR) , but also mt-tRNA Asn , mt-tRNA Lys , mt-tRNA Ala and other (Borthwick et al, 2006;Chinnery et al, 1997;Moraes et al, 1993;Pulkes et al, 2003;Seibel et al, 1994;Spagnolo et al, 2001;Sternberg et al, 2001).…”

The novel mitochondrial tRNAAsn gene mutation m.5709T>C produces ophthalmoparesis and respiratory impairment

“…Heterogeneous clinical presentations can be divided into two groups: an early onset syndromic disease leading to lethal mitochondrial encephalomyopathy 13 or multi-organ failure, 14 and an adult onset phenotype characterized by cPEO, myopathy and a neurological syndrome resembling MERRF (myoclonus epilepsy and RRF). [8][9][10][11][12] As expected, mutations resulting in severe phenotypes or fatal outcome were present at almost homoplasmic levels in blood and skeletal muscle (497%), whereas mutation load appeared lower in adult-onset patients, ranging from 46 to 80%. In our proband, the level of heteroplasmy in leukocytes was moderately low, whereas the mutation appeared largely heteroplasmic in skeletal muscle tissue.…”

Mitochondrial tRNA Mutations: Clinical and Functional Perturbations

“…97 The tRNA Leu(CUN) G12315A mutation, 98 and the tRNA Asn mutations C5703T, 99 and C5698T, 100 have been detected in patients with CPEO and myopathy, however the tRNA Asn A5692G mutation has been associated only with CPEO. 101 A tRNA Ala A5628G mutation has been detected in a patient with ophthalmoplegia and dysphagia. 102 The tRNA Tyr 5885delT, 103 and G5877A 104 heteroplasmic mutations have been associated with familial chronic progressive external ophthalmoplegia.…”

“…The mutation was heteroplasmic in muscle (79%) but undetectable in other tissues. 163 The tRNA Asn mutations C5703T, 99 and C5698T 100,101 have been associated with fatigability and progressive external ophthalmoplegia. The tRNA Glu C14710T mutation has been observed in a patient with mitochondrial myopathy and marked retinopathy.…”