| 1. |
- Roos, Sara, 1979, et al.
(författare)
-
Subnormal levels of POLgA cause inefficient initiation of light-strand DNA synthesis and lead to mitochondrial DNA deletions and progressive external ophthalmoplegia
- 2013
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 22:12, s. 2411-2422
-
Tidskriftsartikel (refereegranskat)abstract
- The POLG1 gene encodes the catalytic subunit of mitochondrial DNA (mtDNA) polymerase γ (POLγ). We here describe a sibling pair with adult-onset progressive external ophthalmoplegia, cognitive impairment and mitochondrial myopathy characterized by DNA depletion and multiple mtDNA deletions. The phenotype is due to compound heterozygous POLG1 mutations, T914P and the intron mutation c.3104 + 3A > T. The mutant genes produce POLγ isoforms with heterozygous phenotypes that fail to synthesize longer DNA products in vitro. However, exon skipping in the c.3104 + 3A > T mutant is not complete, and the presence of low levels of wild-type POLγ explains patient survival. To better understand the underlying pathogenic mechanisms, we characterized the effects of POLγ depletion in vitro and found that leading-strand DNA synthesis is relatively undisturbed. In contrast, initiation of lagging-strand DNA synthesis is ineffective at lower POLγ concentrations that uncouples leading strand from lagging-strand DNA synthesis. In vivo, this effect leads to prolonged exposure of the heavy strand in its single-stranded conformation that in turn can cause the mtDNA deletions observed in our patients. Our findings, thus, suggest a molecular mechanism explaining how POLγ mutations can cause mtDNA deletions in vivo.
|
|
| 2. |
- Andersson Grönlund, Marita, 1959-, et al.
(författare)
-
Ophthalmological findings in children and young adults with genetically verified mitochondrial disease
- 2010
-
Ingår i: British Journal of Ophthalmology. - : BMJ Publishing Group Ltd. - 0007-1161 .- 1468-2079. ; 94:1, s. 121-127
-
Tidskriftsartikel (refereegranskat)abstract
- AIM: To describe ophthalmological phenotypes in patients with mitochondrial disease and known genotypes.METHODS: A retrospective study was performed on 59 patients (29 male, 30 female) with a mean age of 11.8 years who had mitochondrial disease with known DNA mutations. Fifty-seven of the 59 subjects underwent a detailed ophthalmological examination including visual acuity (VA), eye motility, refraction, slit-lamp examination, ophthalmoscopy and, in almost one-half of the cases, a full-field electroretinogram (ERG).RESULTS: Forty-six (81%) of the patients had one or more ophthalmological findings such as ptosis (n = 16), reduced eye motility (n = 22) including severe external ophthalmoplegia (n = 9), strabismus (n = 4), nystagmus (n = 9), low VA (n = 21), refractive errors (n = 26), photophobia (n = 4), and partial or total optic atrophy (n = 25). Pigmentation in the macula and/or periphery was noted in 16 patients. In 10/27 investigated individuals with full field ERG, retinal dystrophy was recorded in six different genotypes representing Kearns-Sayre syndrome (n = 5), Leigh syndrome (n = 1), Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) (n = 1), Myoclonus epilepsy with red ragged fibres (MERRF) (n = 1), Leber hereditary optic neuropathy (n = 1) and mitochondrial myopathy (n = 1).CONCLUSION: The results show that a majority of patients with mitochondrial disorders have ophthalmological abnormalities. We recommend that an ophthalmological examination, including ERG, be performed on all children and adolescents who are suspected of having a mitochondrial disease.
|
|
| 3. |
- Björkman, Kristoffer, et al.
(författare)
-
Broad phenotypic variability in patients with complex I deficiency due to mutations in NDUFS1 and NDUFV1.
- 2015
-
Ingår i: Mitochondrion. - : Elsevier BV. - 1872-8278 .- 1567-7249. ; 21, s. 33-40
-
Tidskriftsartikel (refereegranskat)abstract
- We report clinical, metabolic, genetic and neuroradiological findings in five patients from three different families with isolated complex I deficiency. Genetic analysis revealed mutations in NDUFS1 in three patients and in NDUFV1 in two patients. Four of the mutations are novel and affect amino acid residues that either are invariant among species or conserved in their properties. The presented clinical courses are characterized by leukoencephalopathy or early death and expand the already heterogeneous phenotypic spectrum. A literature review was performed, showing that patients with mutations in NDUFS1 in general have a worse prognosis than patients with mutations in NDUFV1.
|
|
| 4. |
- 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.
|
|
| 5. |
- Darin, Niklas, 1964, et al.
(författare)
-
Mitochondrial myopathy with exercise intolerance and retinal dystrophy in a sporadic patient with a G583A mutation in the mt tRNA(phe) gene
- 2006
-
Ingår i: Neuromuscular disorders : NMD. - : Elsevier BV. - 0960-8966 .- 1873-2364. ; 16:8, s. 504-6
-
Tidskriftsartikel (refereegranskat)abstract
- We describe a second patient with the 583G>A mutation in the tRNA(phe) gene of mitochondrial DNA (mtDNA). This 17-year-old girl had a mitochondrial myopathy with exercise intolerance and an asymptomatic retinopathy. Muscle investigations showed occasional ragged red fibers, 30% cytochrome c oxidase (COX)-negative fibers, and reduced activities of complex I+IV in the respiratory chain. The mutation was heteroplasmic (79%) in muscle but undetectable in other tissues. Analysis of single muscle fibers revealed a significantly higher level of mutated mtDNA in COX-negative fibers. Our study indicates that the 583G>A mutation is pathogenic and expands the clinical spectrum of this mutation.
|
|
| 6. |
- Horvath, Rita, et al.
(författare)
-
Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy.
- 2009
-
Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 132:Pt 11, s. 3165-74
-
Tidskriftsartikel (refereegranskat)abstract
- Childhood-onset mitochondrial encephalomyopathies are usually severe, relentlessly progressive conditions that have a fatal outcome. However, a puzzling infantile disorder, long known as 'benign cytochrome c oxidase deficiency myopathy' is an exception because it shows spontaneous recovery if infants survive the first months of life. Current investigations cannot distinguish those with a good prognosis from those with terminal disease, making it very difficult to decide when to continue intensive supportive care. Here we define the principal molecular basis of the disorder by identifying a maternally inherited, homoplasmic m.14674T>C mt-tRNA(Glu) mutation in 17 patients from 12 families. Our results provide functional evidence for the pathogenicity of the mutation and show that tissue-specific mechanisms downstream of tRNA(Glu) may explain the spontaneous recovery. This study provides the rationale for a simple genetic test to identify infants with mitochondrial myopathy and good prognosis.
|
|
| 7. |
- Kollberg, Gittan, 1963, et al.
(författare)
-
A novel homozygous RRM2B missense mutation in association with severe mtDNA depletion.
- 2009
-
Ingår i: Neuromuscular disorders : NMD. - : Elsevier BV. - 0960-8966. ; 19:2, s. 147-50
-
Tidskriftsartikel (refereegranskat)abstract
- This report describes two brothers, both deceased in infancy, with severe depletion of mitochondrial DNA (mtDNA) in muscle tissue. Both had feeding difficulties, failure to thrive, severe muscular hypotonia and lactic acidosis. One of the boys developed a renal proximal tubulopathy. A novel homozygous c.686 G-->T missense mutation in the RRM2B gene, encoding the p53-inducible ribonucleotide reductase subunit (p53R2), was identified. This is the third report on mutations in RRM2B associated with severe mtDNA depletion, which further highlights the importance of de novo synthesis of deoxyribonucleotides (dNTPs) for mtDNA maintenance.
|
|
| 8. |
- Kollberg, Gittan, 1963, et al.
(författare)
-
Low frequency of mtDNA point mutations in patients with PEO associated with POLG1 mutations.
- 2005
-
Ingår i: European journal of human genetics : EJHG. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 13:4, s. 463-9
-
Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial myopathy in progressive external ophthalmoplegia (PEO) has been associated with POLG1 mutations. POLG1 encodes the catalytic alpha subunit of polymerase gamma and is the only polymerase known to be involved in mtDNA replication. It has two functionally different domains, one polymerase domain and one exonuclease domain with proofreading activity. In this study we have investigated whether mtDNA point mutations are involved, directly or indirectly, in the pathogenesis of PEO. Muscle biopsy specimens from patients with POLG1 mutations, affecting either the exonuclease or the polymerase domain, were investigated. Single cytochrome c oxidase (COX)-deficient muscle fibers were dissected and screened for clonally expanded mtDNA point mutations using a sensitive denaturing gradient gel electrophoresis analysis, in which three different regions of mtDNA, including five different tRNA genes, were investigated. To screen for randomly distributed mtDNA point mutations in muscle, two regions of mtDNA including deletion breakpoints were investigated by high-fidelity PCR, followed by cloning and sequencing. Long-range PCR revealed multiple mtDNA deletions in all the patients but not the controls. No point mutations were identified in single COX-deficient muscle fibers. Cloning and sequencing of muscle homogenate identified randomly distributed point mutations at very low frequency in patients and controls (<1:50 000). We conclude that mtDNA point mutations do not appear to be directly or indirectly involved in the pathogenesis of mitochondrial disease in patients with different POLG1 mutations.
|
|
| 9. |
- Kollberg, Gittan, 1963, et al.
(författare)
-
Mitochondrial myopathy and rhabdomyolysis associated with a novel nonsense mutation in the gene encoding cytochrome c oxidase subunit I.
- 2005
-
Ingår i: Journal of neuropathology and experimental neurology. - 0022-3069. ; 64:2, s. 123-8
-
Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial DNA (mtDNA) mutations associated with rhabdomyolysis are rare but have been described in sporadic cases with mutations in the cytochrome b and cytochrome c oxidase (COX) genes and in 3 cases with tRNALeu mutation. We report a novel heteroplasmic G6708A nonsense mutation in the mtDNA COI gene encoding COX subunit I in a 30-year-old woman with muscle weakness, pain, fatigue, and one episode of rhabdomyolysis. Histochemical examination of muscle biopsy specimens revealed reduced COX activity in the majority of the muscle fibers (approximately 90%) and frequent ragged red fibers. Biochemical analysis showed a marked and isolated COX deficiency. Analysis of DNA extracted from single fibers revealed higher levels of the mutation in COX-deficient fibers (> 95%) compared with COX-positive fibers (1%-80%). The mutation was not detected in a skin biopsy, cultured myoblasts, or blood leukocytes. Nor was it identified in blood leukocytes from the asymptomatic mother, indicating a de novo mutation that arose after germ layer differentiation. Western blot analysis and immunohistochemical staining revealed that reduced levels of COX subunit I were accompanied by reduced levels of other mtDNA encoded subunits, as well as nuclear DNA encoded subunit IV, supporting the concept that COX subunit I is essential for the assembly of complex IV in the respiratory chain.
|
|
| 10. |
- Kollberg, Gittan, 1963, et al.
(författare)
-
POLG1 mutations associated with progressive encephalopathy in childhood.
- 2006
-
Ingår i: Journal of neuropathology and experimental neurology. - : Oxford University Press (OUP). - 0022-3069 .- 1554-6578. ; 65:8, s. 758-68
-
Tidskriftsartikel (refereegranskat)abstract
- We have identified compound heterozygous missense mutations in POLG1, encoding the mitochondrial DNA polymerase gamma (Pol gamma), in 7 children with progressive encephalopathy from 5 unrelated families. The clinical features in 6 of the children included psychomotor regression, refractory seizures, stroke-like episodes, hepatopathy, and ataxia compatible with Alpers-Huttenlocher syndrome. Three families harbored a previously reported A467T substitution, which was found in compound with the earlier described G848S or the W748S substitution or a novel R574W substitution. Two families harbored the W748S change in compound with either of 2 novel mutations predicted to give an R232H or M1163R substitution. Muscle morphology showed mitochondrial myopathy with cytochrome c oxidase (COX)-deficient fibers in 4 patients. mtDNA analyses in muscle tissue revealed mtDNA depletion in 3 of the children and mtDNA deletions in the 2 sibling pairs. Neuropathologic investigation in 3 children revealed widespread cortical degeneration with gliosis and subcortical neuronal loss, especially in the thalamus, whereas there were only subcortical neurodegenerative findings in another child. The results support the concept that deletions as well as depletion of mtDNA are involved in the pathogenesis of Alpers-Huttenlocher syndrome and add 3 new POLG1 mutations associated with an early-onset neurodegenerative disease.
|
|
