title: 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.affiliation: Laboratoire de Biochimie, Hôpital de Bicêtre, Assistance Publique - Hôpitaux de Paris, 78 Rue du Général Leclerc, 94275 Le Kremlin Bicêtre Cedex, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Gaignard
authors.forename: Minal
authors.initials: M
authors.lastname: Menezes
authors.forename: Manuel
authors.initials: M
authors.lastname: Schiff
authors.forename: Aurélien
authors.initials: A
authors.lastname: Bayot
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Rak
authors.forename: Hélène
authors.initials: H
authors.lastname: Ogier de Baulny
authors.forename: Chen-Hsien
authors.initials: CH
authors.lastname: Su
authors.forename: Mylene
authors.initials: M
authors.lastname: Gilleron
authors.forename: Anne
authors.initials: A
authors.lastname: Lombes
authors.forename: Heni
authors.initials: H
authors.lastname: Abida
authors.forename: Alexander
authors.initials: A
authors.lastname: Tzagoloff
authors.forename: Lisa
authors.initials: L
authors.lastname: Riley
authors.forename: Sandra T
authors.initials: ST
authors.lastname: Cooper
authors.forename: Kym
authors.initials: K
authors.lastname: Mina
authors.forename: Padma
authors.initials: P
authors.lastname: Sivadorai
authors.forename: Mark R
authors.initials: MR
authors.lastname: Davis
authors.forename: Richard J N
authors.initials: RJ
authors.lastname: Allcock
authors.forename: Nina
authors.initials: N
authors.lastname: Kresoje
authors.forename: Nigel G
authors.initials: NG
authors.lastname: Laing
authors.forename: David R
authors.initials: DR
authors.lastname: Thorburn
authors.forename: Abdelhamid
authors.initials: A
authors.lastname: Slama
authors.forename: John
authors.initials: J
authors.lastname: Christodoulou
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
mesh_terms: D000595:Amino Acid Sequence; D002675:Child, Preschool; D003241:Consanguinity; D045304:Cytochromes c / Q000235:genetics* / Q000378:metabolism; D003575:Cytochromes c1 / Q000235:genetics* / Q000378:metabolism; D004579:Electron Transport; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D005816:Genetic Complementation Test; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D007328:Insulin / Q000494:pharmacology; D007506:Iron-Sulfur Proteins / Q000235:genetics / Q000378:metabolism; D007662:Ketosis / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D021122:Protein Subunits / Q000235:genetics* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D012867:Skin / Q000201:enzymology / Q000473:pathology
chemical_list: C014059:CYC1 protein, S cerevisiae; D007328:Insulin; D007506:Iron-Sulfur Proteins; D021122:Protein Subunits; D029701:Saccharomyces cerevisiae Proteins; D045304:Cytochromes c; D003575:Cytochromes c1
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