Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
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Gene/Protein
Disease
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Target Concepts:
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Query: UMLS:C0751651 (
mitochondrial disease
)
1,844
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
We describe the case of a woman in whom combination of a mitochondrial (
MT-CYB
) and a nuclear (SDHB) mutation was associated with clinical and metabolic features suggestive of a
mitochondrial disorder
. The mutations impaired overall energy metabolism in the patient's muscle and fibroblasts and increased cellular susceptibility to oxidative stress. To clarify the contribution of each mutation to the phenotype, mutant yeast strains were generated. A significant defect in strains carrying the Sdh2 mutation, either alone or in combination with the cytb variant, was observed. Our data suggest that the SDHB mutation was causative of the
mitochondrial disorder
in our patient with a possible cumulative contribution of the
MT-CYB
variant. To our knowledge, this is the first association of bi-genomic variants in the mtDNA and in a nuclear gene encoding a subunit of complex II.
...
PMID:Additive effect of nuclear and mitochondrial mutations in a patient with mitochondrial encephalomyopathy. 2573 12
Complex III (CIII) deficiency is one of the least common oxidative phosphorylation defects associated to
mitochondrial disease
. CIII constitutes the center of the mitochondrial respiratory chain, as well as a crossroad for several other metabolic pathways. For more than 10 years, of all the potential candidate genes encoding structural subunits and assembly factors, only three were known to be associated to CIII defects in human pathology. Thus, leaving many of these cases unresolved. These first identified genes were
MT-CYB
, the only CIII subunit encoded in the mitochondrial DNA; BCS1L, encoding an assembly factor, and UQCRB, a nuclear-encoded structural subunit. Nowadays, thanks to the fast progress that has taken place in the last 3-4 years, pathological changes in seven more genes are known to be associated to these conditions. This review will focus on the strategies that have permitted the latest discovery of mutations in factors that are necessary for a correct CIII assembly and activity, in relation with their function. In addition, new data further establishing the molecular role of LYRM7/MZM1L as a chaperone involved in CIII biogenesis are provided.
...
PMID:Nuclear gene mutations as the cause of mitochondrial complex III deficiency. 2591 18
We previously observed an unexpected fivefold (35 vs. 200 days) difference in the survival of respiratory chain complex III (CIII) deficient Bcs1l
p.S78G
mice between two congenic backgrounds. Here, we identify a spontaneous homoplasmic mtDNA variant (m.G14904A, mt-Cyb
p.D254N
), affecting the CIII subunit cytochrome b (
MT-CYB
), in the background with short survival. We utilize maternal inheritance of mtDNA to confirm this as the causative variant and show that it further decreases the low CIII activity in Bcs1l
p.S78G
tissues to below survival threshold by 35 days of age. Molecular dynamics simulations predict D254N to restrict the flexibility of
MT-CYB
ef loop, potentially affecting RISP dynamics. In Rhodobacter cytochrome bc
1
complex the equivalent substitution causes a kinetics defect with longer occupancy of RISP head domain towards the quinol oxidation site. These findings represent a unique case of spontaneous mitonuclear epistasis and highlight the role of mtDNA variation as modifier of
mitochondrial disease
phenotypes.
...
PMID:A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice. 3194 67
