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

  • Am J Hum Genet. 2013 Aug 8;93(2):384-9. doi: 10.1016/j.ajhg.2013.06.015.
Pauline Gaignard  1 ,  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
Affiliations
  • 1. Laboratoire de Biochimie, Hôpital de Bicêtre, Assistance Publique - Hôpitaux de Paris, 78 Rue du Général Leclerc, 94275 Le Kremlin Bicêtre Cedex, France.
PMID: 23910460 DOI: 10.1016/j.ajhg.2013.06.015
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.