A Missense Mutation of Cytochrome Oxidase Subunit II Causes Defective Assembly and Myopathy
We report the first missense mutation in the mtDNA gene for subunit II of cytochrome c oxidase (COX). The mutation was identified in a 14-year-old boy with a proximal myopathy and lactic acidosis. Muscle histochemistry and mitochondrial respiratory-chain enzymology demonstrated a marked reduction in...
Saved in:
Published in | American journal of human genetics Vol. 65; no. 4; pp. 1030 - 1039 |
---|---|
Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Chicago, IL
Elsevier Inc
01.10.1999
University of Chicago Press The American Society of Human Genetics |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | We report the first missense mutation in the mtDNA gene for subunit II of cytochrome
c oxidase (COX). The mutation was identified in a 14-year-old boy with a proximal myopathy and lactic acidosis. Muscle histochemistry and mitochondrial respiratory-chain enzymology demonstrated a marked reduction in COX activity. Immunohistochemistry and immunoblot analyses with COX subunit–specific monoclonal antibodies showed a pattern suggestive of a primary mtDNA defect, most likely involving
CO II, for COX subunit II (COX II). mtDNA-sequence analysis demonstrated a novel heteroplasmic T→A transversion at nucleotide position 7,671 in
CO II. This mutation changes a methionine to a lysine residue in the middle of the first N-terminal membrane-spanning region of COX II. The immunoblot studies demonstrated a severe reduction in cross-reactivity, not only for COX II but also for the mtDNA-encoded subunit COX III and for nuclear-encoded subunits Vb, VIa, VIb, and VIc. Steady-state levels of the mtDNA-encoded subunit COX I showed a mild reduction, but spectrophotometric analysis revealed a dramatic decrease in COX I–associated heme
a
3 levels. These observations suggest that, in the COX protein, a structural association of COX II with COX I is necessary to stabilize the binding of heme
a
3 to COX I. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0002-9297 1537-6605 |
DOI: | 10.1086/302590 |