ABSTRACT
DJ-1 mutations are associated to early-onset Parkinson's disease and accounts for about 1-2% of the genetic forms. The protein is involved in many biological processes and its role in mitochondrial regulation is gaining great interest, even if its function in mitochondria is still unclear. We describe a 47-year-old woman affected by a multisystem disorder characterized by progressive, early-onset parkinsonism plus distal spinal amyotrophy, cataracts and sensory-neural deafness associated with a novel homozygous c.461C>A [p.T154K] mutation in DJ-1. Patient's cultured fibroblasts showed low ATP synthesis, high ROS levels and reduced amount of some subunits of mitochondrial complex I; biomarkers of oxidative stress also resulted abnormal in patient's blood. The clinical pattern of multisystem involvement and the biochemical findings in our patient highlight the role for DJ-1 in modulating mitochondrial response against oxidative stress.
Subject(s)
Fibroblasts/metabolism , Oxidative Stress/genetics , Parkinson Disease/genetics , Protein Deglycase DJ-1/genetics , Adenosine Triphosphate/biosynthesis , Electron Transport Complex I/genetics , Electron Transport Complex I/metabolism , Female , Fibroblasts/pathology , Homozygote , Humans , Middle Aged , Mitochondria/genetics , Mitochondria/metabolism , Mutation , Parkinson Disease/pathology , Reactive Oxygen Species/metabolismABSTRACT
NDUFB11, a component of mitochondrial complex I, is a relatively small integral membrane protein, belonging to the "supernumerary" group of subunits, but proved to be absolutely essential for the assembly of an active complex I. Mutations in the X-linked nuclear-encoded NDUFB11 gene have recently been discovered in association with two distinct phenotypes, i.e. microphthalmia with linear skin defects and histiocytoid cardiomyopathy. We report on a male with complex I deficiency, caused by a de novo mutation in NDUFB11 and displaying early-onset sideroblastic anemia as the unique feature. This is the third report that describes a mutation in NDUFB11, but all are associated with a different phenotype. Our results further expand the molecular spectrum and associated clinical phenotype of NDUFB11 defects.
Subject(s)
Acidosis, Lactic/genetics , Anemia, Sideroblastic/genetics , Electron Transport Complex I/genetics , Microphthalmos/genetics , Acidosis, Lactic/complications , Acidosis, Lactic/physiopathology , Anemia, Sideroblastic/complications , Anemia, Sideroblastic/physiopathology , Child , DNA, Mitochondrial/genetics , Electron Transport Complex I/deficiency , Genetic Predisposition to Disease , Humans , Male , Microphthalmos/physiopathology , Mutation , Pedigree , Phenotype , Tyrosine-tRNA LigaseABSTRACT
Mutations in KARS, which encodes for both mitochondrial and cytoplasmic lysyl-tRNA synthetase, have been so far associated with three different phenotypes: the recessive form of Charcot-Mary-Tooth polyneuropathy, the autosomal recessive nonsyndromic hearing loss and the last recently described condition related to congenital visual impairment and progressive microcephaly. Here we report the case of a 14-year-old girl with severe cardiomyopathy associated to mild psychomotor delay and mild myopathy; moreover, a diffuse reduction of cytochrome C oxidase (COX, complex IV) and a combined enzymatic defect of complex I (CI) and complex IV (CIV) was evident in muscle biopsy. Using the TruSight One sequencing panel we identified two novel mutations in KARS. Both mutations, never reported previously, occur in a highly conserved region of the catalytic domain and displayed a dramatic effect on KARS stability. Structural analysis confirmed the pathogenic role of the identified variants. Our findings confirm and emphasize that mt-aminoacyl-tRNA synthetases (mt-ARSs) enzymes are related to a broad clinical spectrum due to their multiple and still unknown functions.
Subject(s)
Cardiomyopathy, Hypertrophic/genetics , Lysine-tRNA Ligase/genetics , Mitochondrial Diseases/genetics , Psychomotor Disorders/genetics , Adolescent , Cardiomyopathy, Hypertrophic/complications , Cardiomyopathy, Hypertrophic/pathology , Electron Transport/genetics , Female , Genetic Predisposition to Disease , Humans , Mitochondria/genetics , Mitochondria/pathology , Mitochondrial Diseases/complications , Mitochondrial Diseases/pathology , Mutation , Phenotype , Psychomotor Disorders/complications , Psychomotor Disorders/pathologyABSTRACT
A multidisciplinary strategy was used to identify the molecular defect in a family with Leigh syndrome (LS). The propositus presented severe developmental delay, an ataxic-spastic gait and seizures. She died at 3.5 y of age from cardiorespiratory arrest. Postmortem examination disclosed pathological features typical of LS. A 12-y-old sister is affected with the same disease. Respiratory chain enzyme complex activities in skeletal muscle biopsy were normal. Adenosine triphosphate (ATP) synthesis during oxidative phosphorylation in skin fibroblasts mitochondria showed a severely hampered ATP production. Mitochondrial DNA sequencing revealed a new mutation in the ATPase 6 gene (T9176G). Site-directed mutagenesis in Escherichia coli strains was used to measure H+ pumping and ATP synthesis. Results were comparable to findings obtained in human cells. These data corroborate the use of E. coli strains as a feasible "animal" model for functional studies in pathogenic mutations of the ATPase 6 gene.
Subject(s)
Escherichia coli/enzymology , Leigh Disease/genetics , Mitochondrial Proton-Translocating ATPases/genetics , Mutation , Child , Child, Preschool , Humans , PedigreeABSTRACT
Sixteen unrelated Southern European patients with the mitochondrial depletion syndrome (MDS) were analyzed for mutations in the TK2 and DGUOK genes. Three novel mutations were identified in TK2 (R183G, R254X, and 142insG). When we analyzed additional genes involved in the dNTPs pool, such as SLC25A19 (DNC) and NT5M (d-NT2), we did not detect mutations. The current study suggest that scanning the TK2, DGUOK, SLC25A19, and NT5M genes is likely to help about 10% of MDS families in terms of genetic counseling. Also, our findings indicate that genotype-phenotype correlations are not straightforward in MDS.
Subject(s)
DNA, Mitochondrial/genetics , DNA, Mitochondrial/metabolism , Mitochondrial Diseases/genetics , Age of Onset , Child , Child, Preschool , DNA Mutational Analysis/methods , Europe , Female , Humans , Infant , Male , Mitochondria, Muscle/enzymology , Mitochondria, Muscle/genetics , Mitochondria, Muscle/pathology , Mitochondrial Diseases/enzymology , Mitochondrial Diseases/mortality , Mitochondrial Diseases/pathology , Mutation , Phosphotransferases (Alcohol Group Acceptor)/genetics , Retrospective Studies , Syndrome , Thymidine Kinase/geneticsABSTRACT
In Danes we replicated the 3'APOB-VNTR gene/longevity association study previously carried out in Italians, by which the Small alleles (less than 35 repeats) had been identified as frailty alleles for longevity. In Danes, neither genotype nor allele frequencies differed between centenarians and 20-64-year-old subjects. However, when Danish and Italian data were compared, a significant difference (p = 0.0004) was found between the frequencies of Small alleles in youths, which disappeared in centenarians (p = 0.290). Furthermore, the demographic-genetic approach revealed in Danes a significant gene-sex interaction relevant to Long alleles (more than 37 repeats). The different findings in Denmark and Italy suggest that gene/longevity associations are population-specific, and heavily affected by the population-specific genetic and environmental history.