Novel TTC19 mutation in a family with severe psychiatric manifestations and complex III deficiency

Nogueira, Célia; Barros, José; Sá, María José; Azevedo, Luı́sa; Taipa, Ricardo; Torraco, Alessandra; Meschini, Maria Chiara; Verrigni, Daniela; Nesti, Claudia; Rizza, Teresa; Teixeira, João; Carrozzo, Rosalba; Pires, Manuel Melo; Vilarinho, Laura; Santorelli, Filippo M.

doi:10.1007/s10048-013-0361-1

Cited by 42 publications

(44 citation statements)

References 22 publications

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“…For BCS1L mutations, common presentations include: muscle hypotonia, hepatopathy, renal tubulopathy, and organic acid accumulation (De Lonlay et al, 2001, Ramos-Arroyo et al, 2009). Mutations in TTC19 have been noted to cause cerebral and cerebellar atrophy (Ghezzi et al, 2011, Morino et al, 2014, Nogueira et al, 2013). Whereas for MT-CYB mutations, presentations include: severe exercise intolerance, myoglobinuria and encephalopathies (Keightley et al, 2000).…”

Section: Resultsmentioning

confidence: 99%

Metabolic flexibility of mitochondrial respiratory chain disorders predicted by computer modelling

Zieliński

Smith

et al. 2016

Mitochondrion

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Mitochondrial respiratory chain dysfunction causes a variety of life-threatening diseases affecting about 1 in 4300 adults. These diseases are genetically heterogeneous, but have the same outcome; reduced activity of mitochondrial respiratory chain complexes causing decreased ATP production and potentially toxic accumulation of metabolites. Severity and tissue specificity of these effects varies between patients by unknown mechanisms and treatment options are limited. So far most research has focused on the complexes themselves, and the impact on overall cellular metabolism is largely unclear. To illustrate how computer modelling can be used to better understand the potential impact of these disorders and inspire new research directions and treatments, we simulated them using a computer model of human cardiomyocyte mitochondrial metabolism containing over 300 characterised reactions and transport steps with experimental parameters taken from the literature. Overall, simulations were consistent with patient symptoms, supporting their biological and medical significance. These simulations predicted: complex I deficiencies could be compensated using multiple pathways; complex II deficiencies had less metabolic flexibility due to impacting both the TCA cycle and the respiratory chain; and complex III and IV deficiencies caused greatest decreases in ATP production with metabolic consequences that parallel hypoxia. Our study demonstrates how results from computer models can be compared to a clinical phenotype and used as a tool for hypothesis generation for subsequent experimental testing. These simulations can enhance understanding of dysfunctional mitochondrial metabolism and suggest new avenues for research into treatment of mitochondrial disease and other areas of mitochondrial dysfunction.

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Section: Resultsmentioning

confidence: 99%

Metabolic flexibility of mitochondrial respiratory chain disorders predicted by computer modelling

Zieliński

Smith

et al. 2016

Mitochondrion

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“…Conditions attributed to CIII deficiency (OMIM #124000) are uncommon, with wide ranging clinical variability. Clinical presentations can include lactic acidosis, sensorineural loss, liver failure, LHON, developmental delay, cardiomyopathies and encephalopathy [80][81][82][83]. In addition, mutations in genes encoding CIII assembly factors have also been identified [84,85].…”

Section: Oxphos Complex IIImentioning

confidence: 99%

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

2016

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SynopsisMitochondria provide the main source of energy to eukaryotic cells, oxidizing fats and sugars to generate ATP . Mitochondrial fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two metabolic pathways which are central to this process. Defects in these pathways can result in diseases of the brain, skeletal muscle, heart and liver, affecting approximately 1 in 5000 live births. There are no effective therapies for these disorders, with quality of life severely reduced for most patients. The pathology underlying many aspects of these diseases is not well understood; for example, it is not clear why some patients with primary FAO deficiencies exhibit secondary OXPHOS defects. However, recent findings suggest that physical interactions exist between FAO and OXPHOS proteins, and that these interactions are critical for both FAO and OXPHOS function. Here, we review our current understanding of the interactions between FAO and OXPHOS proteins and how defects in these two metabolic pathways contribute to mitochondrial disease pathogenesis.Key words: disease, mitochondria, protein complex assembly, protein interactions, supercomplex. MITOCHONDRIAL METABOLISMMitochondria occupy almost all human cell types and are involved in essential metabolic and cellular processes, including calcium and iron homoeostasis, apoptosis, innate immunity and haeme biosynthesis [1]. However, the primary function of mitochondria is the production of energy in the form of ATP [2][3][4]. ATP is the body's energy currency, playing vital roles in cell differentiation, growth and reproduction, thermogenesis and powering the contraction of muscles for movement [1]. In humans, ATP is produced by two different processes; through the breakdown of glucose or other sugars in Abbreviations: ACAD9, acyl-CoA dehydrogenase 9; BN-PAGE, blue native polyacrylamide gel electrophoresis; CACT, carnitine acylcarnitine translocase; CI, oxidative phosphorylation complex I (NADH: ubiquinone oxidoreductase, EC 1.6.5.3); CII, oxidative phosphorylation complex II (succinate: ubiquinone oxidoreductase, EC 1.3.5.1); CIII, oxidative phosphorylation complex III (ubiquinol: ferricytochrome c oxidoreductase, EC 1.10.2.2); CIV, oxidative phosphorylation complex IV (cytochrome c oxidase, EC 1.9.3.1); COPP , complex one phylogenetic profile; CPT1, carnitine O-palmitoyltransferase 1; CPT2, carnitine O-palmitoyltransferase 2; CV, OXPHOS complex V (FoF 1 -ATP synthetase, EC; 3.6.3.14); ECHS1, enoyl-CoA hydratase, short chain 1, mitochondrial; ECI1, enoyl-CoA delta isomerase, 1; ETF, electron transfer flavoprotein; ETFA, electron transfer flavoprotein alpha subunit; ETFB, electron transfer flavoprotein beta subunit; ETF-QO, electron transfer flavoprotein: ubiquinone oxidoreductase; FAD, flavin adenine dinucleotide; FADH 2 , reduced flavin adenine dinucleotide; FAO, fatty acid β-oxidation; H 2 O, water; HADH, hydroxyacyl-CoA dehydrogenase; KAT, 3-ketoacyl-CoA thiolase, mitochondrial; LCAD, long chain acyl-CoA dehydrogenase; LCEH, long chain enoyl-CoA hydra...

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“…The clinical presentation of patients with BCS1L mutations varies greatly with some mutations being associated with tubulopathy, encephalopathy and liver failure [9], others with GRACILE syndrome ( g rowth r etardation, a minoaciduria, c holestasis, i ron overload, l actic acidosis and e arly death, MIM 603358) [12], with isolated encephalopathy [13] or with Björnstad syndrome characterized by sensorineural deafness associated with short brittle hair (MIM 262000) [14]. Mutations in TTC19 have been shown to cause encephalopathy with variable age of onset and rate of progression, which in some patients is associated with severe psychiatric manifestations [10], [15]. Mutations in LYRM7 are associated with early onset encephalopathy [11].…”

Section: Introductionmentioning

confidence: 99%

Mutations in the UQCC1-Interacting Protein, UQCC2, Cause Human Complex III Deficiency Associated with Perturbed Cytochrome b Protein Expression

et al. 2013

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Mitochondrial oxidative phosphorylation (OXPHOS) is responsible for generating the majority of cellular ATP. Complex III (ubiquinol-cytochrome c oxidoreductase) is the third of five OXPHOS complexes. Complex III assembly relies on the coordinated expression of the mitochondrial and nuclear genomes, with 10 subunits encoded by nuclear DNA and one by mitochondrial DNA (mtDNA). Complex III deficiency is a debilitating and often fatal disorder that can arise from mutations in complex III subunit genes or one of three known complex III assembly factors. The molecular cause for complex III deficiency in about half of cases, however, is unknown and there are likely many complex III assembly factors yet to be identified. Here, we used Massively Parallel Sequencing to identify a homozygous splicing mutation in the gene encoding Ubiquinol-Cytochrome c Reductase Complex Assembly Factor 2 (UQCC2) in a consanguineous Lebanese patient displaying complex III deficiency, severe intrauterine growth retardation, neonatal lactic acidosis and renal tubular dysfunction. We prove causality of the mutation via lentiviral correction studies in patient fibroblasts. Sequence-profile based orthology prediction shows UQCC2 is an ortholog of the Saccharomyces cerevisiae complex III assembly factor, Cbp6p, although its sequence has diverged substantially. Co-purification studies show that UQCC2 interacts with UQCC1, the predicted ortholog of the Cbp6p binding partner, Cbp3p. Fibroblasts from the patient with UQCC2 mutations have deficiency of UQCC1, while UQCC1-depleted cells have reduced levels of UQCC2 and complex III. We show that UQCC1 binds the newly synthesized mtDNA-encoded cytochrome b subunit of complex III and that UQCC2 patient fibroblasts have specific defects in the synthesis or stability of cytochrome b. This work reveals a new cause for complex III deficiency that can assist future patient diagnosis, and provides insight into human complex III assembly by establishing that UQCC1 and UQCC2 are complex III assembly factors participating in cytochrome b biogenesis.

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Novel TTC19 mutation in a family with severe psychiatric manifestations and complex III deficiency

Cited by 42 publications

References 22 publications

Metabolic flexibility of mitochondrial respiratory chain disorders predicted by computer modelling

Metabolic flexibility of mitochondrial respiratory chain disorders predicted by computer modelling

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

Mutations in the UQCC1-Interacting Protein, UQCC2, Cause Human Complex III Deficiency Associated with Perturbed Cytochrome b Protein Expression

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