Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0751651 (mitochondrial disease)
 1,844 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a recent paper (Agsteribbe et al. (1993) Biochem. Biophys. Res. Commun. 193, 146-154) we suggested deficiency of heat shock protein 60 (hsp60) as the possible cause of a systemic mitochondrial encephalomyopathy with multiple deficiency of mitochondrial enzymes. In this paper we present new data which strongly support this hypothesis. Hsp60 deficiency appeared to be not a common side effect of impaired mitochondrial metabolism as eight out of ten fibroblast cultures from patients with systemic mitochondrial myopathy contained normal quantities of the protein. The low steady state amount of hsp60 in the fibroblasts of our patient is caused by decreased synthesis of the protein and not by its enhanced degradation indicating that the hsp60 deficiency is indeed a primary defect. Processing of hsp60 but not of other mitochondrial proteins is markedly retarded in the patient cells. Other functional properties of the patient hsp60 like the assembly of hsp60 monomers to the native 14mer complex and the affinity of this complex to denatured protein are not impaired. Our results underline that a primary defect in hsp60 synthesis and/or processing causing a low steady state amount of hsp60 is the molecular basis of this mitochondrial disorder. The presented data provide for the first time substantial evidence that deficiency of a heat shock protein can give rise to pathological conditions in man.
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PMID:Decreased synthesis and inefficient mitochondrial import of hsp60 in a patient with a mitochondrial encephalomyopathy. 798 29

Whole exome sequencing was used to investigate the genetic cause of mitochondrial disease in two siblings with a syndrome of congenital lamellar cataracts associated with nephrocalcinosis, medullary cysts and 3-methylglutaconic aciduria. Autosomal recessive inheritance in a gene encoding a mitochondrially targeted protein was assumed; the only variants which satisfied these criteria were c.1882C>T (p.Arg628Cys) and c.1915G>A (p.Glu639Lys) in the CLPB gene, encoding a heat shock protein/chaperonin responsible for disaggregating mitochondrial and cytosolic proteins. Functional studies, including quantitative PCR (qPCR) and Western blot, support pathogenicity of these mutations. Furthermore, molecular modelling suggests that the mutations disrupt interactions between subunits so that the CLPB hexamer cannot form or is unstable, thus impairing its role as a protein disaggregase. We conclude that accumulation of protein aggregates underlies the development of cataracts and nephrocalcinosis in CLPB deficiency, which is a novel genetic cause of 3-methylglutaconic aciduria. A common mitochondrial cause for 3-methylglutaconic aciduria appears to be disruption of the architecture of the mitochondrial membranes, as in Barth syndrome (tafazzin deficiency), Sengers syndrome (acylglycerol kinase deficiency) and MEGDEL syndrome (impaired remodelling of the mitochondrial membrane lipids because of SERAC1 mutations). We now propose that perturbation of the mitochondrial membranes by abnormal protein aggregates leads to 3-methylglutaconic aciduria in CLPB deficiency.
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PMID:Bi-allelic CLPB mutations cause cataract, renal cysts, nephrocalcinosis and 3-methylglutaconic aciduria, a novel disorder of mitochondrial protein disaggregation. 2559 26