| 1. |
- Björkman, Kristoffer, et al.
(författare)
-
Genotype-phenotype correlations in patients with complex I deficiency due to mutations in NDUFS1 and NDUFV1
- 2014
-
Ingår i: Euromit 2014, 15-19 juni, Tampere, Finland.
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Objectives: To study genotype-phenotype correlations in genes encoding complex I electron input module subunits. Materials and methods: We studied five patients with isolated complex I deficiency, three with NDUFS1 mutations and two with NDUFV1 mutations. A literature review of all reported cases of mutations in the affected genes was performed. Results: The literature review revealed pathological mutations in NDUFS1 for 18 patients in 17 families and correspondingly in NDUFV1 for 26 patients in 19 families. Unpublished clinical data for our five patients were added. Our study showed quite variable clinical courses; death before two years of age was seen in 41% of patients while 18% were alive at seven years. There was a significant difference between the NDUFS1 and NDUFV1 groups for clinical onset and life-span. Mutations in NDUFS1 were linked to a worse clinical course with earlier onset and earlier death. Conclusions: Genotype-phenotype correlations in patients with mutations affecting the genes that encode the electron input module of complex I vary, but patients with NDUFS1 mutation tend to have a worse clinical course than patients with NDUFV1 mutation. Identifying the mutations is of importance for accurate prognostic information and genetic counseling.
|
|
| 2. |
- Kollberg, Gittan, 1963, et al.
(författare)
-
Transient restoration of succinate dehydrogenase activity after rhabdomyolysis in iron-sulphur cluster deficiency myopathy
- 2011
-
Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966 .- 1873-2364. ; 21:2, s. 115-120
-
Tidskriftsartikel (refereegranskat)abstract
- Myopathy with exercise intolerance and deficiency of iron sulphur cluster proteins is caused by an intronic IVS5+382 G > C mutation in ISCU, the gene encoding the iron sulphur cluster assembly protein (IscU). The mutation causes alternative splicing resulting in a truncated protein and severely reduced levels of IscU protein in muscle tissue. Disease manifestations include muscle fatigability, dyspnoea, cardiac palpitations and episodic myoglobinuria. Muscle tissue of these patients demonstrates marked histochemical succinate dehydrogenase deficiency and accumulation of iron in muscle fibres, which are morphological hallmarks of the disease. A biopsy specimen from a patient, two months after a severe attack of rhabdomyolysis, revealed regenerating muscle with normal succinate dehydrogenase activity and only minor iron accumulation, whereas another biopsy obtained nine years after the episode showed the typical hallmarks of the disease. The apparent explanation for the normal succinate dehydrogenase activity during regeneration was a markedly increased level of IscU protein in regenerating muscle tissue and an increase in normally spliced ISCU transcripts in the patient. The results have implications for diagnosis of the disease based on muscle biopsy findings and support the concept that an increase of normally spliced ISCU by RNA modulating therapy may be a therapeutic possibility for these patients.
|
|
| 3. |
- Ostergaard, Elsebet, et al.
(författare)
-
A novel missense mutation in SUCLG1 associated with mitochondrial DNA depletion, encephalomyopathic form, with methylmalonic aciduria.
- 2010
-
Ingår i: European journal of pediatrics. - : Springer Science and Business Media LLC. - 1432-1076 .- 0340-6199. ; 169:2, s. 201-5
-
Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial DNA depletion, encephalomyopathic form, with methylmalonic aciduria is associated with mutations in SUCLA2, the gene encoding a beta subunit of succinate-CoA ligase, where 17 patients have been reported. Mutations in SUCLG1, encoding the alpha subunit of the enzyme, have been reported in only one family, where a homozygous 2 bp deletion was associated with fatal infantile lactic acidosis. We here report a patient with a novel homozygous missense mutation in SUCLG1, whose phenotype is similar to that of patients with SUCLA2 mutations.
|
|
| 4. |
- Pontarin, Giovanna, et al.
(författare)
-
Deoxyribonucleotide metabolism in cycling and resting human fibroblasts with a missense mutation in p53R2, a subunit of ribonucleotide reductase.
- 2011
-
Ingår i: The Journal of biological chemistry. - 1083-351X.
-
Tidskriftsartikel (refereegranskat)abstract
- Ribonucleotide reduction provides deoxynucleotides for nuclear and mitochondrial (mt) DNA replication and DNA repair. In cycling mammalian cells the reaction is catalyzed by two proteins, R1 and R2. A third protein, p53R2, with the same function as R2 occurs in minute amounts. In quiescent cells, p53R2 replaces the absent R2. In humans genetic inactivation of p53R2 causes early death with mtDNA depletion, especially in muscle. We found that cycling fibroblasts from a patient with a lethal mutation in p53R2 contained a normal amount of mtDNA and showed normal growth, ribonucleotide reduction and dNTP pools. However, when made quiescent by prolonged serum starvation the mutant cells strongly down-regulated ribonucleotide reduction, decreased their dCTP and dGTP pools and virtually abolished the catabolism of dCTP in substrate cycles. mtDNA was not affected. Also nuclear DNA synthesis and the cell-cycle regulated enzymes R2 and thymidine kinase 1 decreased strongly, but the mutant cell populations retained unexpectedly larger amounts of the two enzymes than the controls. This difference was probably due to their slightly larger fraction of S-phase cells and therefore not related to the absence of p53R2 activity. We conclude that loss of p53R2 affects ribonucleotide reduction only in resting cells and there leads to a decrease of dNTP catabolism by substrate cycles that counterweighs the loss of anabolic activity. We speculate that this compensatory mechanism suffices to maintain mtDNA in fibroblasts but not in muscle cells with a larger content of mtDNA necessary for their high energy requirements.
|
|
| 5. |
- Roos, Sara, 1979, et al.
(författare)
-
A novel mitochondrial tRNA Arg mutation resulting in an anticodon swap in a patient with mitochondrial encephalomyopathy.
- 2013
-
Ingår i: European journal of human genetics : EJHG. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813. ; 21:5, s. 571-3
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- We report a mutation in the anticodon of the tRNA(Arg) gene (m.10437G>A), resulting in an anticodon swap from GCU to ACU, which is the anticodon of tRNA(Trp), in a boy with mitochondrial encephalomyopathy. Enzyme histochemical analysis of muscle tissue and biochemical analysis of isolated muscle mitochondria demonstrated cytochrome c oxidase (COX) deficiency. Restriction fragment length polymorphism analysis showed that 90% of muscle and 82% of urinary epithelium mtDNA harbored the mutation. The mutation was not identified in blood, fibroblasts, hair roots, or buccal epithelial cells and it was absent in the asymptomatic mother, suggesting that it was a de novo mutation. Single-fiber PCR analysis showed that the proportion of mutated mtDNA correlated with enzyme histochemical COX deficiency. This mutation adds to the three previously described disease-causing mutations in tRNA(Arg), but it is the first mutation occurring in the anticodon of tRNA(Arg).European Journal of Human Genetics advance online publication, 11 July 2012; doi:10.1038/ejhg.2012.153.
|
|
| 6. |
- Sofou, Kalliopi, et al.
(författare)
-
Phenotypic and genotypic variability in Alpers syndrome.
- 2012
-
Ingår i: European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. - : Elsevier BV. - 1532-2130. ; 16:4, s. 379-89
-
Tidskriftsartikel (refereegranskat)abstract
- Alpers syndrome is one of the most common phenotypes of mitochondrial disorders in early childhood and has been associated with pathogenic mutations in POLG1.
|
|
