Universität zu Köln

Hallmann, Kerstin, Kudin, Alexei P., Zsurka, Gabor ORCID: 0000-0002-6379-849X, Kornblum, Cornelia, Reimann, Jens, Stueve, Burkhard, Waltz, Stephan, Hattingen, Elke ORCID: 0000-0002-8392-9004, Thiele, Holger, Nuernberg, Peter, Rueb, Cornelia, Voos, Wolfgang, Kopatz, Jens, Neumann, Harald and Kunz, Wolfram S. ORCID: 0000-0003-1113-3493 (2016). Loss of the smallest subunit of cytochrome c oxidase, COX8A, causes Leigh-like syndrome and epilepsy. Brain, 139. S. 338 - 346. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2156

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Abstract

Isolated cytochrome c oxidase (complex IV) deficiency is one of the most frequent respiratory chain defects in humans and is usually caused by mutations in proteins required for assembly of the complex. Mutations in nuclear-encoded structural subunits are very rare. In a patient with Leigh-like syndrome presenting with leukodystrophy and severe epilepsy, we identified a homozygous splice site mutation in COX8A, which codes for the ubiquitously expressed isoform of subunit VIII, the smallest nuclear-encoded subunit of complex IV. The mutation, affecting the last nucleotide of intron 1, leads to aberrant splicing, a frame-shift in the highly conserved exon 2, and decreased amount of the COX8A transcript. The loss of the wild-type COX8A protein severely impairs the stability of the entire cytochrome c oxidase enzyme complex and manifests in isolated complex IV deficiency in skeletal muscle and fibroblasts, similar to the frequent c. 845_846delCT mutation in the assembly factor SURF1 gene. Stability and activity of complex IV could be rescued in the patient's fibroblasts by lentiviral expression of wild-type COX8A. Our findings demonstrate that COX8A is indispensable for function of human complex IV and its mutation causes human disease.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hallmann, Kerstin UNSPECIFIED UNSPECIFIED UNSPECIFIED Kudin, Alexei P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zsurka, Gabor UNSPECIFIED orcid.org/0000-0002-6379-849X UNSPECIFIED Kornblum, Cornelia UNSPECIFIED UNSPECIFIED UNSPECIFIED Reimann, Jens UNSPECIFIED UNSPECIFIED UNSPECIFIED Stueve, Burkhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Waltz, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED Hattingen, Elke UNSPECIFIED orcid.org/0000-0002-8392-9004 UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Rueb, Cornelia UNSPECIFIED UNSPECIFIED UNSPECIFIED Voos, Wolfgang UNSPECIFIED UNSPECIFIED UNSPECIFIED Kopatz, Jens UNSPECIFIED UNSPECIFIED UNSPECIFIED Neumann, Harald UNSPECIFIED UNSPECIFIED UNSPECIFIED Kunz, Wolfram S. UNSPECIFIED orcid.org/0000-0003-1113-3493 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-286126
DOI:	10.1093/brain/awv357
Journal or Publication Title:	Brain
Volume:	139
Page Range:	S. 338 - 346
Date:	2016
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2156
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DISEASE; ENCEPHALOMYOPATHY; BIOGENESIS; MUTATIONS; EVOLUTION; COX6B1; VIII Multiple languages Clinical Neurology; Neurosciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/28612