Mutations in CYC1, Encoding Cytochrome c1 Subunit of Respiratory Chain Complex III, Cause Insulin-Responsive Hyperglycemia

Gaignard, Pauline; Menezes, Minal; Schiff, Manuel; Bayot, Aurélien; Rak, Malgorzata; Baulny, Hélène Ogier de; Su, Chen-Hsien; Gilleron, Mylène; Lombès, Anne; Abida, Heni; Tzagoloff, Alexander; Riley, Lisa G.; Cooper, Sandra T.; Mina, Kym; Sivadorai, Padma; Davis, Mark; Allcock, Richard J. N.; Kresoje, Nina; Laing, Nigel G.; Thorburn, David R.; Slama, Abdelhamid; Christodoulou, John; Rustin, Pierre

doi:10.1016/j.ajhg.2013.06.015

Cited by 64 publications

(50 citation statements)

References 15 publications

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“…Variations in this gene have only been previously reported in two other patients with similar presentation. One of these patients is also of Sri Lankan origin and she is homozygous for the same variant found in our patient (Gaignard et al 2013). …”

Section: Case Reportmentioning

confidence: 91%

“…These effects are also reproduced when the variant is inserted at the orthologous position in the yeast CYC1 ortholog. The variant is thought to affect the tertiary structure of the subunit, resulting in increased susceptibility to proteolysis and/or decreased ability to assemble with the other CIII subunits (Gaignard et al 2013).…”

Section: Discussionmentioning

confidence: 99%

“…3). This is a rare, previously reported pathogenic variant (Gaignard et al 2013) observed with a frequency of 8.251e-06 in ExAC and not observed in dbSNP (version 142), NHLBI ESP, or our in-house genome database. The variant was predicted to be deleterious by all tested prediction software: a CADD score of 27.1 (Kircher et al 2014); a SIFT prediction score of 0.001 (cutoff ¼ 0.05) (Kumar et al 2009); a PROVEAN prediction score of À4 (cutoff ¼ À2.5) (Choi et al 2012); and a Polyphen2 "probably damaging" score of 1.000 (Adzhubei et al 2013).…”

Section: Case Reportmentioning

confidence: 99%

“…Cytochrome c 1 is the hemecontaining subunit of CIII and facilitates the transfer of electrons from the Rieske complex to cytochrome C. The two reported patients both presented with recurrent episodes of ketoacidosis and insulin-responsive hyperglycemia in the context of intercurrent illness (Gaignard et al 2013). Both patients also responded well to fluid resuscitation and insulin administration.…”

Section: Introductionmentioning

confidence: 99%

“…Ten subunits are encoded by nuclear DNA (CYC1 (OMIM #615453), UQCRFS1, UQCRQ (#615159), UQCRC1, UQCRC2 (#615160), UQCRH, UQCRB (#615158), UQCR10, UQCR11, subunit IX) and cytochrome b (MT-CYB, OMIM #516020) is encoded by the mitochondrial DNA. There are also a number of associated proteins required for CIII's proper assembly and functioning (Fernández-Vizarra and Zeviani 2015;Gaignard et al 2013).…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial Complex III Deficiency with Ketoacidosis and Hyperglycemia Mimicking Neonatal Diabetes

et al. 2016

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Section: Case Reportmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Case Reportmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mitochondrial Complex III Deficiency with Ketoacidosis and Hyperglycemia Mimicking Neonatal Diabetes

et al. 2016

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Mitochondrial disorders of the OXPHOS system

2020

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Mitochondrial disorders are amongst the most frequent inborn errors of metabolism, their primary cause being the dysfunction of the oxidative phosphorylation system (OXPHOS). OXPHOS is composed of the electron transport chain (ETC), formed by four multimeric enzymes and two mobile electron carriers, plus an ATP synthase (also called complex V). The ETC performs the redox reactions involved in cellular respiration while generating the proton motive force used by complex V to synthesize ATP. OXPHOS biogenesis involves multiple steps, starting from the expression of genes encoded in physically separated genomes, namely the mitochondrial and nuclear DNA, to the coordinated assembly of components and cofactors building each individual complex and eventually the supercomplexes. The genetic cause underlying around half of the diagnosed mitochondrial disease cases is currently known. Many of these cases result from pathogenic variants in genes encoding structural subunits or additional factors directly involved in the assembly of the ETC complexes. Here we review the historical and most recent findings concerning the clinical phenotypes and the molecular pathological mechanisms underlying this particular group of disorders.

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Phenotypic variation of TTC19‐deficient mitochondrial complex III deficiency: A case report and literature review

Mordaunt

Jolley

Balasubramaniam

et al. 2015

American J of Med Genetics Pt A

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Isolated mitochondrial respiratory chain complex III deficiency has been described in a heterogeneous group of clinical presentations in children and adults. It has been associated with mutations in MT-CYB, the only mitochondrial DNA encoded subunit, as well as in nine nuclear genes described thus far: BCS1L, TTC19, UQCRB, UQCRQ, UQCRC2, CYC1, UQCC2, LYRM7, and UQCC3. BCS1L, TTC19, UQCC2, LYRM7, and UQCC3 are complex III assembly factors. We report on an 8-year-old girl born to consanguineous Iraqi parents presenting with slowly progressive encephalomyopathy, severe failure to thrive, significant delays in verbal and communicative skills and bilateral retinal cherry red spots on fundoscopy. SNP array identified multiple regions of homozygosity involving 7.5% of the genome. Mutations in the TTC19 gene are known to cause complex III deficiency and TTC19 was located within the regions of homozygosity. Sequencing of TTC19 revealed a homozygous nonsense mutation at exon 6 (c.937C > T; p.Q313X). We reviewed the phenotypes and genotypes of all 11 patients with TTC19 mutations leading to complex III deficiency (including our case). The consistent features noted are progressive neurodegeneration with Leigh-like brain MRI abnormalities. Significant variability was observed however with the age of symptom onset and rate of disease progression. The bilateral retinal cherry red spots and failure to thrive observed in our patient are unique features, which have not been described, in previously reported patients with TTC19 mutations. Interestingly, all reported TTC19 mutations are nonsense mutations. The severity of clinical manifestations however does not specifically correlate with the residual complex III enzyme activities.

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Mutations in CYC1, Encoding Cytochrome c1 Subunit of Respiratory Chain Complex III, Cause Insulin-Responsive Hyperglycemia

Cited by 64 publications

References 15 publications

Mitochondrial Complex III Deficiency with Ketoacidosis and Hyperglycemia Mimicking Neonatal Diabetes

Mitochondrial Complex III Deficiency with Ketoacidosis and Hyperglycemia Mimicking Neonatal Diabetes

Mitochondrial disorders of the OXPHOS system

Phenotypic variation of TTC19‐deficient mitochondrial complex III deficiency: A case report and literature review

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