Alternative titles; symbols
HGNC Approved Gene Symbol: MT-TW
SNOMEDCT: 16851005, 29570005, 447292006; ICD10CM: G31.82;
The mitochondrial tRNA for tryptophan is encoded by nucleotides 5512-5576.
In a patient with adult-onset dementia, chorea, cerebellar ataxia, deafness, and peripheral neuropathy, Nelson et al. (1995) identified a heteroplasmic 5549G-A transition in the MTTW gene. The mutation had a widespread distribution in autopsy tissues. Postmortem examination showed diffuse neuronal loss and gliosis throughout the brain.
In a family in which the proband had a progressive neurologic disorder and his brother died in infancy of Leigh syndrome (256000), Santorelli et al. (1997) identified a 1-bp insertion (5537insT) in the MTTW gene. Muscle biopsy from the proband showed subsarcolemmal proliferation of mitochondria and decreased activities of oxidative metabolism enzymes, in particular complex IV. The mutation was abundant in tissues from the proband and his brother (greater than 92%), and less abundant (42 to 89%) in 4 maternal relatives, 3 of whom had neuropsychiatric disturbances.
Tulinius et al. (2003) reported a boy with Leigh syndrome who had the 5537insT mutation. From infancy, he was irritable and had hypotonia. Later, neurologic features included nystagmus, optic atrophy, seizures, delayed motor development, and mental retardation. Skeletal muscle analysis showed a profound COX deficiency and complex I deficiency. The mutation was found in a high proportion (greater than 95%) in blood, liver, and muscle tissue of the patient, and in blood of the patient's mother (81%).
Silvestri et al. (1998) reported a family with a late-onset myopathy caused by a 5521G-A transition in the MTTW gene. A 68-year-old man had progressive bilateral ptosis and fatigue from the age of 50 years, and his mother and 1 brother were reportedly similarly affected. Muscle biopsy of the proband showed a mitochondrial myopathy with many COX-negative ragged-red fibers and severe COX deficiency. The mutation was heteroplasmic in muscle (98%), but absent in leukocytes. Silvestri et al. (1998) noted the differences from previously reported phenotypes caused by mutation in the MTTW gene.
In a girl with a neurogastrointestinal syndrome, Maniura-Weber et al. (2004) identified a 5532G-A transition in the MTTW gene. The patient presented at 1 year of age with recurrent vomiting and failure to thrive. Later in childhood she had leg discomfort, cognitive regression, seizures, and incontinence. Other features included sensorineural deafness, ptosis, ophthalmoplegia, pigmentary retinopathy, and constricted visual fields. She was a small child (below third percentile for height and weight), and continued to have feeding difficulties with constipation and diarrhea. Muscle biopsy showed COX-negative fibers and low activity of complexes I and IV. The mutation was present in muscle (92%), fibroblasts (37%), and blood (21%), and at low levels in blood from the patient's mother (7%) and unaffected brother (9%).
In a 13-year-old boy with a mitochondrial encephalocardiomyopathy, Sacconi et al. (2008) identified a heteroplasmic 5545C-T transition in the MTTW gene, which was present at unusually low levels (less than 25%) in affected tissues. In vitro functional expression studies in cybrid cell lines showed that the pathogenic threshold for the mutation was between 4 and 8%, suggesting a dominant mechanism of action. The mutation affects the central base of the anticodon triplet of tRNA-Trp, which may alter the codon specificity of the affected tRNA. The patient presented at age 5 months with hypertrophic cardiomyopathy, truncal hypotonia, and lactic acidosis. Skeletal muscle showed defective respiratory chain complex activity. He progressively lost acquired developmental milestones, developed seizures, and, at 3 years of age, he showed slowly progressive chorea. Brain MRI showed mild diffuse brain atrophy and bilateral hyperintensities in the putamen. At 13 years of age, he was microcephalic, hypotonic but hyperreflexic, ataxic and dysmetric, and had choreic movements. Sacconi et al. (2008) emphasized the unusual finding of a mitochondrial mutation that behaves like a true dominant allele.
In a female infant with a fatal mitochondrial encephalomyopathy, Smits et al. (2010) identified a 5556G-A transition in the MTTW gene. The mutation occurred at a highly conserved nucleotide in the variable region of the tRNA-Trp structure. The patient had feeding problems from birth, and psychomotor regression was noted at age 7 months. She developed severe constipation and failure to thrive. At age 10 months, she was hypotonic and unable to sit without support, and laboratory studies showed lactic acidosis. She died of respiratory insufficiency at age 13 months. Patient fibroblasts and skeletal muscle showed severely decreased activities of mitochondrial respiratory complexes I, III, and IV (15-59% of control values). The mutant load was 92% in fibroblasts and 93% in skeletal muscle, whereas it was absent in the mother's blood. In vitro studies of patient cells showed a marked reduction in mitochondrial protein synthesis, and Northern blot analysis showed reduced levels of mutant tRNA-Trp (29-33%). In addition, gel electrophoresis indicated an abnormal conformation of the mutant protein.
Maniura-Weber, K., Taylor, R. W., Johnson, M. A., Chrzanowska-Lightowlers, Z., Morris, A. A. M., Charlton, C. P. J., Turnbull, D. M., Bindoff, L. A. A novel point mutation in the mitochondrial tRNA(Trp) gene produces a neurogastrointestinal syndrome. Europ. J. Hum. Genet. 12: 509-512, 2004. [PubMed: 15054399] [Full Text: https://doi.org/10.1038/sj.ejhg.5201185]
Nelson, I., Hanna, M. G., Alsanjari, N., Scaravilli, F., Morgan-Hughes, J. A., Harding, A. E. A new mitochondrial DNA mutation associated with progressive dementia and chorea: a clinical, pathological, and molecular genetic study. Ann. Neurol. 37: 400-403, 1995. [PubMed: 7695240] [Full Text: https://doi.org/10.1002/ana.410370317]
Sacconi, S., Salviati, L., Nishigaki, Y., Walker, W. F., Hernandez-Rosa, E., Trevisson, E., Delplace, S., Desnuelle, C., Shanske, S., Hirano, M., Schon, E. A., Bonilla, E., De Vivo, D. C., DiMauro, S., Davidson, M. M. A functionally dominant mitochondrial DNA mutation. Hum. Molec. Genet. 17: 1814-1820, 2008. [PubMed: 18337306] [Full Text: https://doi.org/10.1093/hmg/ddn073]
Santorelli, F. M., Tanji, K., Sano, M., Shanske, S., El-Shahawi, M., Kranz-Eble, P., DiMauro, S., De Vivo, D. C. Maternally inherited encephalopathy associated with a single-base insertion in the mitochondrial tRNATrp gene. Ann. Neurol. 42: 256-260, 1997. [PubMed: 9266739] [Full Text: https://doi.org/10.1002/ana.410420220]
Silvestri, G., Rana, M., DiMuzio, A., Uncini, A., Tonali, P., Servidei, S. A late-onset mitochondrial myopathy is associated with a novel mitochondrial DNA (mtDNA) point mutation in the tRNA(Trp) gene. Neuromusc. Disord. 8: 291-295, 1998. [PubMed: 9673981] [Full Text: https://doi.org/10.1016/s0960-8966(98)00037-6]
Smits, P., Mattijssen, S., Morava, E., van den Brand, M., van den Brandt, F., Wijburg, F., Pruijn, G., Smeitink, J., Nijtmans, L., Rodenburg, R., van den Heuvel, L. Functional consequences of mitochondrial tRNA-Trp and tRNA-Arg mutations causing combined OXPHOS defects. Europ. J. Hum. Genet. 18: 324-329, 2010. [PubMed: 19809478] [Full Text: https://doi.org/10.1038/ejhg.2009.169]
Tulinius, M., Moslemi, A.-R., Darin, N., Westerberg, B., Wiklund, L.-M., Holme, E., Oldfors, A. Leigh syndrome with cytochrome-c oxidase deficiency and a single T insertion nt 5537 in the mitochondrial tRNA(Trp) gene. Neuropediatrics 34: 87-91, 2003. [PubMed: 12776230] [Full Text: https://doi.org/10.1055/s-2003-39607]