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Morten K.J.; Cooper J.M.; Brown G.K.; Lake B.D.; PIke D.; Poulton J. 《Human molecular genetics》1993,2(12):2081-2087
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Fu K; Hartlen R; Johns T; Genge A; Karpati G; Shoubridge EA 《Human molecular genetics》1996,5(11):1835-1840
A novel mtDNA point mutation was detected in the tRNAleu(CUN) gene (G to A
at position 12315) in a sporadic patient with chronic progressive external
ophthalmoplegia, ptosis, limb weakness, sensorineural hearing loss and a
pigmentary retinopathy. The mutation disrupts base pairing in the T psi C
stem at a site which has been conserved throughout evolution. Although the
other mtDNA tRNAleu gene (UUR) is a hotspot for mutation, this is the first
pathogenic mutation to be reported in the gene coding for tRNAleu(CUN).
MtDNAs carrying the mutation constituted 94% of total mtDNAs in two
separate muscle biopsies. Single fibre analysis showed that skeletal muscle
fibres without detectable cytochrome c oxidase activity (COX-ve fibres)
contained predominantly mutant mtDNAs (93-98%) while fibres with apparently
normal COX activity had up to 90% mutant mtDNAs, demonstrating that the
G12315A mutation is functionally recessive. Immunofluorescence studies with
specific antibodies to mtDNA- or nuclear-encoded subunits of COX were
consistent with a defect in mitochondrial protein translation. The mutation
was not present in blood cells or cultured fibroblasts and surprisingly, it
could not be detected in satellite cells cultured from the patient's
muscle. This pattern, which may by typical of patients who have inherited
new germline pathogenic mtDNA mutations, possibly reflects loss of the
mutation by random genetic drift in mitotic tissues and proliferation of
mitochondria containing the mutant mtDNA in post- mitotic cells. The
absence of mtDNA carrying the mutation in satellite cells suggests that
regeneration of skeletal muscle fibres from satellite cells could restore a
wild-type mtDNA genotype and normal muscle function.
相似文献
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We have identified a new mutation in the tRNA(Lys) gene of mtDNA, in a 49-year-old patient with mitochondrial encephalomyopathy. The mutation is a heteroplasmic G-->A transition at position 8328, which affects the anticodon stem loop at a conserved site. The mutation was neither found in 100 controls nor in the maternal relatives of the patient. The level of mutated mtDNA was 57% in muscle, 13% in fibroblasts, and 10% in lymphocytes. Histochemistry of muscle tissue revealed cytochrome c oxidase-deficient fibers with abnormal accumulation of mitochondria. Biochemistry of muscle mitochondria showed slight cytochrome c oxidase deficiency. The mean ratio of mutant mtDNA to normal mtDNA in cytochrome c oxidase-positive muscle fibers was 59%, whereas a mean ratio of 95% was found in cytochrome c oxidase-negative fibers. The difference between cytochrome c oxidase-positive and cytochrome c oxidase-negative fibers was highly significant (P < 0.001). The mutation was not found in muscle or lymphocytes of the mother and daughter of the proband. This is the first report of a de novo point mutation in the tRNA(Lys) gene in an individual expressing disease and the first report of lack of transmission of the mutation to the offspring of a patient expressing a mitochondrial encephalomyopathy caused by a point mutation in mtDNA. 相似文献
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The relationship between mitochondrial genotype and mitochondrial phenotype in lymphoblasts with a heteroplasmic mtDNA deletion 总被引:2,自引:1,他引:1
Spelbrink Johannes N.; Van Oost Bernard A.; Bogert Coby Van den 《Human molecular genetics》1994,3(11):1989-1997
The relationship between mitochondrial genotype and mitochondrialphenotype was investigated in lymphoblasts derived from a patientwith the Pearson syndrome. In 70% of the mtDNA of this Pearsoncell line a deletion from within the COX II gene to within theND5 gene was present. The deletion led to a reduced expressionof the deleted genes, but the severely lowered synthesis ofe.g. subunlt II of cytochrome c oxidase was not reflected ina significant decrease in the cytochrome c oxidase activity.Moreover, there were no obvious differences between controlcells and Pearson cells regarding the capacity for oxidativephosphorylation. Analysis of the synthesis and assembly of bothnuclearly and mitochondrially encoded subunlts of cytochromec oxidase showed that normally mtDNA-encoded polypeptides areproduced in excess. This overproduction fully explained thediscrepancy between the severe defect in the expression of themitochondrial genome and the normal mitochondrial function inthe Pearson cells. These data demonstrate that the expressionof one or more mitochondrial genes can be reduced specificallyat intermediate percentages of deleted mtDNA. However, the dataalso suggest that whether or not a lower expression of mitochondrialgenes encoding subunits of enzymes involved In oxidative phosphorylationinfluences the normal function of these enzymes depends on therelative abundance of the mitochondrial subunits In tissuesor cells with deleted mtDNA. 相似文献
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Raha S Merante F Shoubridge E Myint AT Tein I Benson L Johns T Robinson BH 《Human mutation》1999,13(3):245-254
Familial hypertrophic ventricular cardiomyopathy has been demonstrated to be associated with a number of mitochondrial DNA (mtDNA) mutations. A fibroblast cell line carrying a mutation in its mtDNA at position 9997 in the gene encoding tRNA glycine was obtained from a patient with hypertrophic cardiomyopathy. To demonstrate that the etiology of this disease was a result of the mtDNA mutation, cybrid clones were constructed by fusion of enucleated patient skin fibroblasts to rho0 osteosarcoma cells. Clones carrying high levels of mutant mtDNA showed predominantly cytochrome c oxidase and complex I deficiency, as well as an elevated lactate/pyruvate (L/P) ratio, a biochemical marker characteristic of respiratory chain deficiencies. Pulse-labeling experiments demonstrated a strong negative correlation between the levels of newly synthesized mtDNA-encoded polypeptides and glycine content. These data suggest that the T9997C mutation in mtDNA is causative of respiratory chain dysfunction when present at high levels of heteroplasmy. 相似文献
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Nephropathy and growth hormone deficiency in a patient with mitochondrial tRNA(Leu(UUR)) mutation.
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T Yorifuji M Kawai T Momoi H Sasaki K Furusho J Muroi K Shimizu Y Takahashi M Matsumura M Nambu T Okuno 《Journal of medical genetics》1996,33(7):621-622
A mitochondrial A 3243 G mutation in the tRNA(Leu(UUR)) gene was first described as a common cause of MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like syndrome). This same mutation is also the cause of a totally different disorder, a subtype of diabetes mellitus which is inherited maternally and often associated with sensorineural hearing loss. In this paper, we report on a Japanese boy with A 3243 G who developed a previously undescribed combination of symptoms, nephropathy and growth hormone deficiency. The patient first presented with short stature and moderate mental retardation. Growth hormone (GH) provocation tests showed deficient growth hormone secretion. During the course of follow up, he presented with progressive nephropathy followed by the development of diabetes mellitus. The results of laboratory tests and renal biopsy were against incidental association of known types of nephropathy. On PCR-RFLP analysis, the percentage of mutated mtDNA was higher in the renal biopsy specimen than 12 peripheral blood leucocytes. Our case suggests that mitochondrial diseases should be taken into account when there is nephropathy of unknown cause. In addition, the presence of growth hormone deficiency may account for part of the mechanism leading to short stature commonly seen in these patients. 相似文献
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De Joanna G Santorelli FM Casali C Brescia-Morra V Perretti A Santoro L 《Journal of human genetics》2000,45(2):109-111
We report a patient who manifested a heterogeneous clinical presentation, including hypertrophic cardiomyopathy and hypothyroidism,
with initially limited central nervous system involvement, and who harbored the mitochondrial (mt)DNA A3243G mutation. MtDNA
analyses also revealed deleted genomes in muscle and blood. This atypical molecular combination may have influenced the clinical
phenotype.
Received: August 5, 1999 / Accepted: October 5, 1999 相似文献
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A novel point mutation in the mitochondrial tRNA(Trp) gene produces a neurogastrointestinal syndrome 总被引:1,自引:0,他引:1
Maniura-Weber K Taylor RW Johnson MA Chrzanowska-Lightowlers Z Morris AA Charlton CP Turnbull DM Bindoff LA 《European journal of human genetics : EJHG》2004,12(6):509-512
We report a novel, heteroplasmic point mutation in the mitochondrial tRNA for tryptophan at position 5532. The mutation was present in all the tissues studied and segregated with the biochemical defect, with higher levels of mutation present in cytochrome c oxidase-deficient muscle fibres. The patient manifested a neurogastrointestinal syndrome with features including failure to thrive, psychomotor retardation, ophthalmoplegia, sensorineural deafness and encephalopathy together with vomiting, diarrhoea and colitis. 相似文献
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Distribution of wild-type and common deletion forms of mtDNA in normal and respiration-deficient muscle fibers from patients with mitochondrial myopathy 总被引:15,自引:1,他引:14
Sciacco Monica; Bonilla Eduardo; Schon Eric A.; DiMauro Salvatore; Moraes Carlos T. 《Human molecular genetics》1994,3(1):13-19
We studied the cellular distribution of both deleted ( 相似文献
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Transmitochondrial cell lines were isolated by fusing mtDNA-less rho
degrees 206 cells with enucleated fibroblasts derived from four members of
a pedigree carrying in their muscle varying proportions of the mutation at
position 3243 in the tRNA(Leu(UUR)) gene associated with the MELAS
encephalomyopathy. The mitochondrial transformants derived from an
asymptomatic individual were all homoplasmic for wild-type mtDNA. The
proportion of wild-type transformants derived from clinically affected
members of the pedigree appeared to decrease in correspondence with an
increase in severity of the clinical symptoms of the cell donor.
Furthermore, the average proportion of wild-type mtDNA in the transformants
derived from each member of the pedigree was very similar to that found in
mtDNA from the fibroblasts of that individual, suggesting that the
distribution of genotypes in the transformants reflected fairly closely
that in the fibroblasts. The genotype and phenotype of ten transformants
derived from one severely affected individual were investigated during
continuous culture up to 17-24 weeks after the transformation step. Six
heteroplasmic clones showed a progressive increase in the proportion of
mutant mtDNA, whereas the mitochondrial genotype remained constant in four
clones apparently homoplasmic for wild-type mtDNA or nearly homoplasmic for
mutant mtDNA. An analysis of the rate of repopulation of rho degrees 206
cells with fibroblast-derived mtDNA revealed a large variability among
different transformants, with the full re-establishment of the control
ratio of mtDNA to nuclear DNA being observed between approximately 6 weeks
and more than 22 weeks after the transformation step. An increase in rate
of O2 consumption generally accompanied the increase in mtDNA copy number
of the transformants, pointing to the important role of the mtDNA copy
number in determining the phenotype of a cell. The observation that a very
small amount of wild-type mtDNA (2 to 5% of the control level), coexisting
with strongly predominant mutant mtDNA, conferred upon the transformants a
substantial respiratory capacity (50% or more) and the evidence of
proportionality between O2 consumption rate and mtDNA copy number, which
occurred at widely different mutant to wild-type mtDNA ratios, strongly
suggest a contribution of the mutant mtDNA to the cell respiratory
competence.
相似文献
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Peiqing He Qingming Wang Xiaochun Hong Haiming Yuan 《American journal of medical genetics. Part A》2023,191(1):70-76
Biallelic pathogenic variants in the TARS2 gene cause combined oxidative phosphorylation deficiency, subtype 21 (COXPD21, MIM #615918), which is a rare mitochondrial encephalomyopathy (ME) characterized by early-onset severe axial hypotonia, limb hypertonia, delayed psychomotor development, epilepsy, and brain anomalies. Currently, eight COXPD21 patients have been reported in the literature, and 11 pathogenic variants in TARS2 have been identified. Here, we report a 2-year-6-month-old Chinese female who presented with severe dystonia, developmental regression, absent speech, and intractable epilepsy. Laboratory examination showed persistently increased serum lactate. Brain MRI showed that the head of the caudate and partial lenticular nucleus were bilateral symmetrical T2-weighted imaging (T2WI) hyperintense and the corpus callosum was very thin. The clinical characteristics pointed to a ME. Trio-based whole-exome sequencing (WES) was employed to detect the causative variants. WES revealed novel compound heterozygous variants, c.470G>C (p.Thr157Arg) and c.2051C>T (p.Arg684Gln), in TARS2 in our patient that were inherited from the mother and father, respectively. Next, we systematically reviewed the available clinical features of COXPD21 patients and noticed that the reduced fetal movement observed in our patient may be a novel phenotype of COXPD21. These findings expand the mutation spectrum of TARS2 and provide insights into the genotype–phenotype relationship in COXPD21 as well as a foundation for its genetic counseling, diagnosis and treatment. 相似文献
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Maternally inherited hearing loss, ataxia and myoclonus associated with a novel point mutation in mitochondrial tRNA Ser(UCN) gene 总被引:3,自引:1,他引:2
Tiranti Valeria; Chariot Patrick; Carella Francesco; Toscano Antonio; Soliveri Paola; Girlanda Paolo; Carrara Franco; Fratta Giovanni Matteo; Reid Fiona M.; Mariotti Caterina; Zeviani Massimo 《Human molecular genetics》1995,4(8):1421-1427
We report on a new maternally-inherited syndrome characterizedby a combination of sensorineural hearing loss, ataxia and myoclonusin a large kindred from Sicily. Hearing loss was the most widespreadand sometimes the only symptom found in family members. Sequenceanalysis of the mitochondrial DNA regions encompassing the tRNAgenes revealed the presence of a heteroplasmic insertion atnucleotide position 7472. The insertion adds a seventh cytosineto a six-cytosine run that is part of the mitochondrial tRNASer(UCN) gene. Conformational analysis showed that this mutationis likely to alter the structure of the T 相似文献
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We have detected a novel mitochondrial mutation in a maternal pedigree, at least 13 of whose members have sensorineural hearing loss of varying severity, but who exhibit no other pathological features. The mutation, at np 7445, converts the 3′ terminal T residue of tRNA-ser(UCN) to a C, and also brings about a silent alteration to the COI stop codon. The mutation destroys an XbaI site, within which a second mutation, at np 7444, has previously been reported in association with Leber's hereditary optic neuropathy. Predominantly mutant mtDNA was found in all 13 family members surveyed, whether or not they are overtly affected by deafness, and some individuals appeared homoplasmic, within the limits of detection. The novel mutation was not found in over 600 normal controls, nor in any of 27 other maternally unrelated individuals with deafness Other mutations found in mitochondrial disorders were also absent from this pedigree. © 1994 Wiley-Liss, Inc. 相似文献
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We previously have characterized a pathogenic mtDNA mutation in the tRNAAsn gene. This mutation (G5703A) was associated with a severe mitochondrial protein synthesis defect and a reduction in steady-state levels of tRNAAsn. We now show that, although transmitochondrial cybrids harboring homoplasmic levels of the mutation do not survive in galactose medium, several galactose-resistant clones could be obtained. These cell lines had restored oxidative phosphorylation function and 2-fold higher steady-state levels of tRNAAsn when compared with the parental mutant cell line. The revertant lines contained apparently homoplasmic levels of the mutation and no other detectable alteration in the tRNAAsn gene. To investigate the origin of the suppression, we transferred mtDNA from the revertants (143B/206 TK-) to a different nuclear background (143B/207 TK-, 8AGr). These new transmitochondrial cybrids became defective once again in oxidative phosphorylation and regained galactose sensitivity. However, galactose-resistant clones could also be obtained by growing the 8AGr transmitochondrial cybrids under selection. Because the original rate of reversion was higher than that expected by a classic second site nuclear mutation, and because of the aneuploid features of these cell lines, we searched for the presence of chromosomal alterations that could be associated with the revertant phenotype. These studies, however, did not reveal any gross changes. Our results suggest that modulation of the dosage or expression of unknown nuclear-coded factor(s) can compensate for a pathogenic mitochondrial tRNA gene mutation, suggesting new strategies for therapeutic intervention. 相似文献
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Deschauer M Neudecker S Müller T Gellerich FN Zierz S 《Molecular genetics and metabolism》2000,70(3):235-237
Phenotypes of individuals with the mitochondrial A3243G mutation and amount of mutant DNA in different tissues can be very variable, but the proportion of mutant DNA was consistantly lower in blood than muscle in previously studied patients. We detected the A3243G mutation in a 54-year-old patient with cardiomyopathy and hearing loss, where the amount of mutant DNA was higher in blood (19%) than in muscle (6%). This shows that the level of A3243G mutation is not always lower in rapidly dividing tissues such as blood than in muscle, as has been presumed until now. 相似文献