Retinitis Pigmentosa and Progressive Sensorineural Hearing Loss Caused by a C12258A Mutation in the Mitochondrial MTTS2 Gene

Abstract

Family ZMK is a large Irish kindred that segregates progressive sensorineural hearing loss and retinitis pigmentosa. The symptoms in the family are almost identical to those observed in Usher syndrome type III. Unlike that in Usher syndrome type III, the inheritance pattern in this family is compatible with dominant, X-linked dominant, or maternal inheritance. Prior linkage studies had resulted in exclusion of most candidate loci and >90% of the genome. A tentative location for a causative nuclear gene had been established on 9q; however, it is notable that no markers were found at zero recombination with respect to the disease gene. The marked variability in symptoms, together with the observation of subclinical muscle abnormalities in a single muscle biopsy, stimulated sequencing of the entire mtDNA in affected and unaffected individuals. This revealed a number of previously reported polymorphisms and/or silent substitutions. However, a C-->A transversion at position 12258 in the gene encoding the second mitochondrial serine tRNA, MTTS2, was heteroplasmic and was found in family members only. This sequence change was not present in 270 normal individuals from the same ethnic background. The consensus C at this position is highly conserved and is present in species as divergent from Homo sapiens as vulture and platypus. The mutation probably disrupts the amino acid-acceptor stem of the tRNA molecule, affecting aminoacylation of the tRNA and thereby reducing the efficiency and accuracy of mitochondrial translation. In summary, the data presented provide substantial evidence that the C12258A mtDNA mutation is causative of the disease phenotype in family ZMK.

Mutations in the mitochondrial tRNASer(AGY) gene are associated with deafness, retinal degeneration, myopathy and epilepsy

“…9 This clustering of mutations within MTTS2 suggests that an intact aminoacyl acceptor stem is of crucial importance for maintaining the unusual secondary structure of mt-tRNA Ser(AGY) , which lacks a DHU loop, and for preserving the correct function of the molecule. Although these pathogenic MTTS2 mutations are associated with a variety of clinical presentations including diabetes mellitus, myopathy, neurodevelopmental delay, encephalopathy and seizures, it is interesting to note that all four are also linked to deafness, [6][7][8] and, like the vast majority of deafness-associated mt-tRNA mutations, 33 both m.12264C4T and m.12261T4C were shown here to exhibit a high threshold for pathogenicity. Two additional MTTS2 sequence variants have also been linked to auditory symptoms; m.12236G4A has been associated with hearing loss 10 and m.12224C4T, associated with haplogroup D4, has been found to modulate the penetrance of hearing loss associated with the MT-RNR1 mutation, m.1555A4G.…”

“…[6][7][8] Interestingly, all four (m.12258C4A, m.12261T4C, m.12262C4A and m.12264C4T) are located within the 3¢-end of the aminoacyl acceptor stem of mt-tRNA Ser(AGY) , whereas a fifth 'probably pathogenic' MTTS2 mutation, m.12207G4A, has been identified within the 5¢ end of this stem. 9 This clustering of mutations within MTTS2 suggests that an intact aminoacyl acceptor stem is of crucial importance for maintaining the unusual secondary structure of mt-tRNA Ser(AGY) , which lacks a DHU loop, and for preserving the correct function of the molecule.…”

“…To date, only two MTTS2 mutations have been reported, for which sufficient evidence exists to support their classification as 'definitely pathogenic' according to recently revised canonical criteria. 4,5 These mutations are m.12258C4A, which can lead to progressive deafness and either diabetes mellitus 6 or retinitis pigmentosa, 7 and m.12262C4A, which has been shown to cause progressive mitochondrial myopathy, deafness and sporadic seizures. 8 A further three MTTS2 mutations have been described: m.12207G4A, which is associated with a MELAS-like phenotype, 9 m.12236G4A, which is linked to non-syndromic hearing impairment, 10 and m.12246C4A, which is associated with chronic intestinal pseudo-obstruction with myopathy and ophthalmoplegia.…”

Defining the Importance of Mitochondrial Gene Defects in Maternally Inherited Diabetes by Sequencing the Entire Mitochondrial Genome

“…The first functional mutation was a C to A substitution at position 12258 in a tRNA serine gene. This mutation has been previously reported (4,11), and was associated with maternally inherited diabetes, sensorineural deafness, cataracts, and cerebellar ataxia. The second mutation was the previously reported T to C substitution at position 14709 in the tRNA glutamic acid gene (5).…”

Mitochondrial disorders: aetiologies, models systems, and candidate therapies

“…Mutations in mitochondrial amino acyl-tRNA synthetases (mt-aaRSs), key players in the translational machinery that link amino acids to their cognate mitochondrial tRNAs, are involved in several disorders [19]. Mutations in specific mitochondrial tRNAs have been reported [20,21]; for example, position 3243 in the mitochondrial tRNA LEU(UUR) underlies 80% of mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS) [21].…”