PMC:4573257 / 24440-26411
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/4573257","sourcedb":"PMC","sourceid":"4573257","source_url":"https://www.ncbi.nlm.nih.gov/pmc/4573257","text":"The two reported subjects both presented with lactic acidosis and evidence of multiple mitochondrial respiratory-chain-complex deficiencies in skeletal muscle, although the clinical presentation was remarkably different. The female individual (73901) presented mainly with a history of life-long exercise intolerance with no cardiac involvement, whereas the male individual (65205) presented with dysmorphic signs, failure to thrive, growth retardation, hypertrophic non-obstructive cardiomyopathy, peripheral neuropathy, and moderate to severe developmental delay in childhood. Interestingly, clinically relevant MTO1 or GTPBP3 variants responsible for a different modification in the mt-tRNA anticodon loop (position 34, “wobble base”) have also been associated with lactic acidosis, multiple respiratory-chain deficiencies, and hypertrophic cardiomyopathy.12,13 The presence of hypertrophic cardiomyopathy as a prominent and common phenotype in all three disorders indicates tissue-specific threshold effects; the heart is specifically vulnerable for a diminished mitochondrial translation rate. The increased sensitivity of cardiac tissue as a consequence of a perturbed mitochondrial translation has recently been recapitulated in an MTO1 mouse model.43,44 It is possible that the higher degree of mt-tRNA hypomodification detected in individual 65205 (Figure 4) and the consequent impairment of mitochondrial translation accounts for the more severe symptoms in this case (Table 1). The latter is also supported by a modestly lowered respiration rate in the 65205 fibroblast (Figure S6), but no detectable changes in oxygen consumption in the 73901 fibroblast. Such non-overlapping phenotypes between individuals harboring variants in the same gene involved in mt-tRNA maturation have been previously reported.45 The spectrum of clinical phenotypes associated with mt-tRNA modification deficiencies, including cases without cardiac disorder,9 is constantly growing.","tracks":[{"project":"2_test","denotations":[{"id":"26189817-22608499-2053358","span":{"begin":862,"end":864},"obj":"22608499"},{"id":"26189817-25434004-2053358","span":{"begin":862,"end":864},"obj":"25434004"},{"id":"26189817-25506927-2053359","span":{"begin":1259,"end":1261},"obj":"25506927"},{"id":"26189817-25552653-2053359","span":{"begin":1259,"end":1261},"obj":"25552653"},{"id":"26189817-25705216-2053360","span":{"begin":1816,"end":1818},"obj":"25705216"},{"id":"26189817-19732863-2053361","span":{"begin":1947,"end":1948},"obj":"19732863"}],"attributes":[{"subj":"26189817-22608499-2053358","pred":"source","obj":"2_test"},{"subj":"26189817-25434004-2053358","pred":"source","obj":"2_test"},{"subj":"26189817-25506927-2053359","pred":"source","obj":"2_test"},{"subj":"26189817-25552653-2053359","pred":"source","obj":"2_test"},{"subj":"26189817-25705216-2053360","pred":"source","obj":"2_test"},{"subj":"26189817-19732863-2053361","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#9c93ec","default":true}]}]}}