Mutations in COA3 cause isolated complex IV deficiency associated with neuropathy, exercise intolerance, obesity, and short stature

Elsebet Ostergaard; Woranontee Weraarpachai; Kirstine Johanne Theresia Ravn; Alfred Peter Born; Lars Jønson; Morten Dunø; Flemming Wibrand; Eric A Shoubridge; John Vissing

doi:10.1136/jmedgenet-2014-102914

Mutations in COA3 cause isolated complex IV deficiency associated with neuropathy, exercise intolerance, obesity, and short stature

Elsebet Ostergaard, Woranontee Weraarpachai, Kirstine Johanne Theresia Ravn, Alfred Peter Born, Lars Jønson, Morten Dunø, Flemming Wibrand, Eric A Shoubridge, John Vissing

Department of Clinical Medicine

32 Citations (Scopus)

Abstract

BACKGROUND: We investigated a subject with an isolated cytochrome c oxidase (COX) deficiency presenting with an unusual phenotype characterised by neuropathy, exercise intolerance, obesity, and short stature.

METHODS AND RESULTS: Blue-native polyacrylamide gel electrophoresis (BN-PAGE) analysis showed an almost complete lack of COX assembly in subject fibroblasts, consistent with the very low enzymatic activity, and pulse-labelling mitochondrial translation experiments showed a specific decrease in synthesis of the COX1 subunit, the core catalytic subunit that nucleates assembly of the holoenzyme. Whole exome sequencing identified compound heterozygous mutations (c.199dupC, c.215A>G) in COA3, a small inner membrane COX assembly factor, resulting in a pronounced decrease in the steady-state levels of COA3 protein. Retroviral expression of a wild-type COA3 cDNA completely rescued the COX assembly and mitochondrial translation defects, confirming the pathogenicity of the mutations, and resulted in increased steady-state levels of COX1 in control cells, demonstrating a role for COA3 in the stabilisation of this subunit. COA3 exists in an early COX assembly complex that contains COX1 and other COX assembly factors including COX14 (C12orf62), another single pass transmembrane protein that also plays a role in coupling COX1 synthesis with holoenzyme assembly. Immunoblot analysis showed that COX14 was undetectable in COA3 subject fibroblasts, and that COA3 was undetectable in fibroblasts from a COX14 subject, demonstrating the interdependence of these two COX assembly factors.

CONCLUSIONS: The mild clinical course in this patient contrasts with nearly all other cases of severe COX assembly defects that are usually fatal early in life, and underscores the marked tissue-specific involvement in mitochondrial diseases.

Original language	English
Journal	Journal of Medical Genetics
Volume	52
Issue number	3
Pages (from-to)	203-7
Number of pages	5
ISSN	0022-2593
DOIs	https://doi.org/10.1136/jmedgenet-2014-102914
Publication status	Published - Mar 2015

Keywords

Adult
Child, Preschool
Cyclooxygenase 1
Cytochrome-c Oxidase Deficiency
Dwarfism
Electron Transport Complex IV
Exercise
Exome
Female
Fibroblasts
Gene Expression Regulation, Enzymologic
Humans
Membrane Proteins
Mitochondrial Proteins
Obesity

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1136/jmedgenet-2014-102914

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Mutations in COA3 cause isolated complex IV deficiency associated with neuropathy, exercise intolerance, obesity, and short stature. / Ostergaard, Elsebet; Weraarpachai, Woranontee; Ravn, Kirstine Johanne Theresia et al.
In: Journal of Medical Genetics, Vol. 52, No. 3, 03.2015, p. 203-7.

Research output: Contribution to journal › Journal article › Research › peer-review

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abstract = "BACKGROUND: We investigated a subject with an isolated cytochrome c oxidase (COX) deficiency presenting with an unusual phenotype characterised by neuropathy, exercise intolerance, obesity, and short stature.METHODS AND RESULTS: Blue-native polyacrylamide gel electrophoresis (BN-PAGE) analysis showed an almost complete lack of COX assembly in subject fibroblasts, consistent with the very low enzymatic activity, and pulse-labelling mitochondrial translation experiments showed a specific decrease in synthesis of the COX1 subunit, the core catalytic subunit that nucleates assembly of the holoenzyme. Whole exome sequencing identified compound heterozygous mutations (c.199dupC, c.215A>G) in COA3, a small inner membrane COX assembly factor, resulting in a pronounced decrease in the steady-state levels of COA3 protein. Retroviral expression of a wild-type COA3 cDNA completely rescued the COX assembly and mitochondrial translation defects, confirming the pathogenicity of the mutations, and resulted in increased steady-state levels of COX1 in control cells, demonstrating a role for COA3 in the stabilisation of this subunit. COA3 exists in an early COX assembly complex that contains COX1 and other COX assembly factors including COX14 (C12orf62), another single pass transmembrane protein that also plays a role in coupling COX1 synthesis with holoenzyme assembly. Immunoblot analysis showed that COX14 was undetectable in COA3 subject fibroblasts, and that COA3 was undetectable in fibroblasts from a COX14 subject, demonstrating the interdependence of these two COX assembly factors.CONCLUSIONS: The mild clinical course in this patient contrasts with nearly all other cases of severe COX assembly defects that are usually fatal early in life, and underscores the marked tissue-specific involvement in mitochondrial diseases.",

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author = "Elsebet Ostergaard and Woranontee Weraarpachai and Ravn, {Kirstine Johanne Theresia} and Born, {Alfred Peter} and Lars J{\o}nson and Morten Dun{\o} and Flemming Wibrand and Shoubridge, {Eric A} and John Vissing",

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doi = "10.1136/jmedgenet-2014-102914",

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T1 - Mutations in COA3 cause isolated complex IV deficiency associated with neuropathy, exercise intolerance, obesity, and short stature

AU - Ostergaard, Elsebet

AU - Weraarpachai, Woranontee

AU - Ravn, Kirstine Johanne Theresia

AU - Born, Alfred Peter

AU - Jønson, Lars

AU - Dunø, Morten

AU - Wibrand, Flemming

AU - Shoubridge, Eric A

AU - Vissing, John

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

PY - 2015/3

Y1 - 2015/3

N2 - BACKGROUND: We investigated a subject with an isolated cytochrome c oxidase (COX) deficiency presenting with an unusual phenotype characterised by neuropathy, exercise intolerance, obesity, and short stature.METHODS AND RESULTS: Blue-native polyacrylamide gel electrophoresis (BN-PAGE) analysis showed an almost complete lack of COX assembly in subject fibroblasts, consistent with the very low enzymatic activity, and pulse-labelling mitochondrial translation experiments showed a specific decrease in synthesis of the COX1 subunit, the core catalytic subunit that nucleates assembly of the holoenzyme. Whole exome sequencing identified compound heterozygous mutations (c.199dupC, c.215A>G) in COA3, a small inner membrane COX assembly factor, resulting in a pronounced decrease in the steady-state levels of COA3 protein. Retroviral expression of a wild-type COA3 cDNA completely rescued the COX assembly and mitochondrial translation defects, confirming the pathogenicity of the mutations, and resulted in increased steady-state levels of COX1 in control cells, demonstrating a role for COA3 in the stabilisation of this subunit. COA3 exists in an early COX assembly complex that contains COX1 and other COX assembly factors including COX14 (C12orf62), another single pass transmembrane protein that also plays a role in coupling COX1 synthesis with holoenzyme assembly. Immunoblot analysis showed that COX14 was undetectable in COA3 subject fibroblasts, and that COA3 was undetectable in fibroblasts from a COX14 subject, demonstrating the interdependence of these two COX assembly factors.CONCLUSIONS: The mild clinical course in this patient contrasts with nearly all other cases of severe COX assembly defects that are usually fatal early in life, and underscores the marked tissue-specific involvement in mitochondrial diseases.

AB - BACKGROUND: We investigated a subject with an isolated cytochrome c oxidase (COX) deficiency presenting with an unusual phenotype characterised by neuropathy, exercise intolerance, obesity, and short stature.METHODS AND RESULTS: Blue-native polyacrylamide gel electrophoresis (BN-PAGE) analysis showed an almost complete lack of COX assembly in subject fibroblasts, consistent with the very low enzymatic activity, and pulse-labelling mitochondrial translation experiments showed a specific decrease in synthesis of the COX1 subunit, the core catalytic subunit that nucleates assembly of the holoenzyme. Whole exome sequencing identified compound heterozygous mutations (c.199dupC, c.215A>G) in COA3, a small inner membrane COX assembly factor, resulting in a pronounced decrease in the steady-state levels of COA3 protein. Retroviral expression of a wild-type COA3 cDNA completely rescued the COX assembly and mitochondrial translation defects, confirming the pathogenicity of the mutations, and resulted in increased steady-state levels of COX1 in control cells, demonstrating a role for COA3 in the stabilisation of this subunit. COA3 exists in an early COX assembly complex that contains COX1 and other COX assembly factors including COX14 (C12orf62), another single pass transmembrane protein that also plays a role in coupling COX1 synthesis with holoenzyme assembly. Immunoblot analysis showed that COX14 was undetectable in COA3 subject fibroblasts, and that COA3 was undetectable in fibroblasts from a COX14 subject, demonstrating the interdependence of these two COX assembly factors.CONCLUSIONS: The mild clinical course in this patient contrasts with nearly all other cases of severe COX assembly defects that are usually fatal early in life, and underscores the marked tissue-specific involvement in mitochondrial diseases.

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KW - Child, Preschool

KW - Cyclooxygenase 1

KW - Cytochrome-c Oxidase Deficiency

KW - Dwarfism

KW - Electron Transport Complex IV

KW - Exercise

KW - Exome

KW - Female

KW - Fibroblasts

KW - Gene Expression Regulation, Enzymologic

KW - Humans

KW - Membrane Proteins

KW - Mitochondrial Proteins

KW - Obesity

U2 - 10.1136/jmedgenet-2014-102914

DO - 10.1136/jmedgenet-2014-102914

M3 - Journal article

C2 - 25604084

SN - 0022-2593

VL - 52

SP - 203

EP - 207

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

IS - 3

ER -

Mutations in COA3 cause isolated complex IV deficiency associated with neuropathy, exercise intolerance, obesity, and short stature

Abstract

Keywords

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