Mitochondrial complex IV deficiency caused by a novel frameshift variant in MT-CO2 associated with myopathy and perturbed acylcarnitine profile

Roos, Sara,1979Gothenburg University,Göteborgs universitet,Institutionen för biomedicin,Institute of Biomedicine (author)

Mitochondrial myopathies are a heterogeneous group of disorders associated with a wide range of clinical phenotypes. We present a 16-year-old girl with a history of exercise intolerance since childhood. Acylcarnitine species suggestive of multiple acyl-CoA dehydrogenase deficiency were found in serum, however genetic analysis did not reveal variants in genes associated with this disorder. Biochemical analyses of skeletal muscle mitochondria revealed an isolated and extremely low activity of cytochrome c oxidase (COX). This finding was confirmed by enzyme histochemistry, which demonstrated an almost complete absence of fibers with normal COX activity. Whole-exome sequencing revealed a single base-pair deletion (m.8088delT) in MT-CO2, which encodes subunit 2 of COX, resulting in a premature stop codon. Restriction fragment length polymorphism-analysis confirmed mtDNA heteroplasmy with high mutant load in skeletal muscle, the only clinically affected tissue, but low levels in other investigated tissues. Single muscle fiber analysis showed segregation of the mutant genotype with respiratory chain dysfunction. Immuno-histochemical studies indicated that the truncating variant in COX2 has an inhibitory effect on the assembly of the COX holoenzyme.

Sofou, Kalliopi (author)
Oldfors Hedberg, Carola,1969Gothenburg University,Göteborgs universitet,Institutionen för biomedicin,Institute of Biomedicine(Swepub:gu)xnordc (author)
Kollberg, Gittan,1963Gothenburg University,Göteborgs universitet,Institutionen för biomedicin,Institute of Biomedicine(Swepub:gu)xkolgi (author)
Lindgren, UlrikaGothenburg University,Göteborgs universitet,Institutionen för biomedicin,Institute of Biomedicine (author)
Thomsen, Christer,1977Gothenburg University,Göteborgs universitet,Institutionen för biomedicin,Institute of Biomedicine(Swepub:gu)xtchrb (author)
Tulinius, Mar,1953Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för pediatrik,Institute of Clinical Sciences, Department of Pediatrics(Swepub:gu)xtulim (author)
Oldfors, Anders,1951Gothenburg University,Göteborgs universitet,Institutionen för biomedicin,Institute of Biomedicine(Swepub:gu)xoland (author)
Göteborgs universitetInstitutionen för biomedicin (creator_code:org_t)

In:European Journal of Human Genetics: Springer Science and Business Media LLC27:2, s. 331-3351018-48131476-5438

By the author/editor: Roos, Sara, 1979; Sofou, Kalliopi; Oldfors Hedberg, ...; Kollberg, Gittan ...; Lindgren, Ulrika; Thomsen, Christe ...; show more...; Tulinius, Mar, 1 ...; Oldfors, Anders, ...; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Medical Genetics

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