title: Mitochondrial complex III deficiency caused by a homozygous UQCRC2 mutation presenting with neonatal-onset recurrent metabolic decompensation.
abstract: Mitochondrial complex III (CIII) deficiency is a relatively rare disease with high clinical and genetic heterogeneity. CIII comprises 11 subunits encoded by one mitochondrial and 10 nuclear genes. Abnormalities of the nuclear genes such as BCS1L and TTC19 encoding mitochondrial assembly factors are well known, but an explanation of the majority of CIII deficiency remains elusive. Here, we report three patients from a consanguineous Mexican family presenting with neonatal onset of hypoglycemia, lactic acidosis, ketosis, and hyperammonemia. We found a homozygous missense mutation in UQCRC2 that encodes mitochondrial ubiquinol-cytochrome c reductase core protein II by whole-exome sequencing combined with linkage analysis. On the basis of structural modeling, the mutation (p.Arg183Trp) was predicted to destabilize the hydrophobic core at the subunit interface of the core protein II homodimer. In vitro studies using fibroblasts from the index patient clearly indicated CIII deficiency, as well as impaired assembly of the supercomplex formed from complexes I, III, and IV. This is the first described human disease caused by a core protein abnormality in mitochondrial CIII.
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. nmiyake@yokohama-cu.ac.jp
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.forename: Shoji
authors.initials: S
authors.lastname: Yano
authors.forename: Chika
authors.initials: C
authors.lastname: Sakai
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Hatakeyama
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Matsushima
authors.forename: Masaaki
authors.initials: M
authors.lastname: Shiina
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Watanabe
authors.forename: James
authors.initials: J
authors.lastname: Bartley
authors.forename: Jose E
authors.initials: JE
authors.lastname: Abdenur
authors.forename: Raymond Y
authors.initials: RY
authors.lastname: Wang
authors.forename: Richard
authors.initials: R
authors.lastname: Chang
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tsurusaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Doi
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Nakashima
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ogata
authors.forename: Yu-Ichi
authors.initials: Y
authors.lastname: Goto
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000140:Acidosis, Lactic / Q000235:genetics; D000328:Adult; D015153:Blotting, Western; D014450:Electron Transport Complex III / Q000172:deficiency / Q000235:genetics*; D059472:Exome; D005260:Female; D008040:Genetic Linkage; D006720:Homozygote; D006801:Humans; D022124:Hyperammonemia / Q000235:genetics; D007003:Hypoglycemia / Q000235:genetics; D007662:Ketosis / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008928:Mitochondria / Q000235:genetics; D028361:Mitochondrial Diseases / Q000175:diagnosis* / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics; D020125:Mutation, Missense; D010375:Pedigree; D011487:Protein Conformation; D017422:Sequence Analysis, DNA
chemical_list: C435491:BCS1L protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C557528:TTC19 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities; D014450:Electron Transport Complex III