Karine Auré, Guillemette Fayet, Ivan Chicherin, Benoit Rucheton, Sandrine Filaut, Anne-Marie Heckel, Julie Eichler, Florence Caillon, Yann Péréon, Nina Entelis, Ivan Tarassov, Anne Lombès (2020) A homoplasmic mitochondrial tRNAPro mutation causing exercise-induced muscle swelling and fatigue. Neurology: Genetics (in press) Neurol Genet 2020;6:e480. doi:10.1212/NXG.0000000000000480
To demonstrate the causal role in disease of the MT-TP m.15992A>T mutation observed in
patients from 5 independent families.
Lactate measurement, muscle histology, and mitochondrial activities in patients; PCR-based
analyses of the size, amount, and sequence of muscle mitochondrial DNA (mtDNA) and
proportion of the mutation; respiration, mitochondrial activities, proteins, translation, transfer
RNA (tRNA) levels, and base modification state in skin fibroblasts and cybrids; and reactive
oxygen species production, proliferation in the absence of glucose, and plasma membrane
potential in cybrids.
All patients presented with severe exercise intolerance and hyperlactatemia. They were associated
with prominent exercise-induced muscle swelling, conspicuous in masseter muscles (2
families), and/or with congenital cataract (2 families). MRI confirmed exercise-induced muscle
edema. Muscle disclosed severe combined respiratory defect. Muscle mtDNA had normal size
and amount. Its sequence was almost identical in all patients, defining the haplotype as J1c10,
and sharing 31 variants, only 1 of which, MT-TP m.15992A>T, was likely pathogenic. The
mutation was homoplasmic in all tissues and family members. Fibroblasts and cybrids with
homoplasmic mutation had defective respiration, low complex III activity, and decreased
tRNAPro amount. Their respiratory complexes amount and tRNAPro aminoacylation appeared
normal. Low proliferation in the absence of glucose demonstrated the relevance of the defects
on cybrid biology while abnormal loss of cell volume when faced to plasma membrane depolarization
provided a link to the muscle edema observed in patients.
The homoplasmic MT-TP m.15992A>T mutation in the J1c10 haplotype causes exerciseinduced
muscle swelling and fatigue.