Mutations in CYC1, encoding cytochrome c1 subunit of respiratory chain complex III, cause insulin-responsive hyperglycemia.

Abstract

Many individuals with abnormalities of mitochondrial respiratory chain complex III remain genetically undefined. Here, we report mutations (c.288G>T [p.Trp96Cys] and c.643C>T [p.Leu215Phe]) in CYC1, encoding the cytochrome c1 subunit of complex III, in two unrelated children presenting with recurrent episodes of ketoacidosis and insulin-responsive hyperglycemia. Cytochrome c1, the heme-containing component of complex III, mediates the transfer of electrons from the Rieske iron-sulfur protein to cytochrome c. Cytochrome c1 is present at reduced levels in the skeletal muscle and skin fibroblasts of affected individuals. Moreover, studies on yeast mutants and affected individuals' fibroblasts have shown that exogenous expression of wild-type CYC1 rescues complex III activity, demonstrating the deleterious effect of each mutation on cytochrome c1 stability and complex III activity.

• Authors: Pauline Gaignard, Minal Menezes, Manuel Schiff, Aurélien Bayot, Malgorzata Rak, Hélène Ogier de Baulny, Chen-Hsien Su, Mylene Gilleron, Anne Lombes, Heni Abida, Alexander Tzagoloff, Lisa Riley, Sandra T Cooper, Kym Mina, Padma Sivadorai, Mark R Davis, Richard J N Allcock, Nina Kresoje, Nigel G Laing, David R Thorburn, Abdelhamid Slama, John Christodoulou, Pierre Rustin
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 93 Issue 2 Pg. 384-9 (Aug 08 2013) ISSN: 1537-6605 [Electronic] United States
• PMID: 23910460 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• CYC1 protein, S cerevisiae
• Insulin
• Iron-Sulfur Proteins
• Protein Subunits
• Saccharomyces cerevisiae Proteins
• Cytochromes c
• Cytochromes c1

Topics

• Amino Acid Sequence
• Child, Preschool
• Consanguinity
• Cytochromes c (genetics, metabolism)
• Cytochromes c1 (genetics, metabolism)
• Electron Transport
• Female
• Fibroblasts (enzymology, pathology)
• Genetic Complementation Test
• Humans
• Hyperglycemia (drug therapy, enzymology, genetics, physiopathology)
• Insulin (pharmacology)
• Iron-Sulfur Proteins (genetics, metabolism)
• Ketosis (drug therapy, enzymology, genetics, physiopathology)
• Male
• Mitochondria (enzymology, genetics)
• Models, Molecular
• Molecular Sequence Data
• Mutation
• Protein Subunits (genetics, metabolism)
• Saccharomyces cerevisiae (enzymology, genetics)
• Saccharomyces cerevisiae Proteins (genetics, metabolism)
• Skin (enzymology, pathology)