Mutations in
C19orf12
have been recently identified as the molecular genetic cause of a subtype of neurodegeneration with brain iron accumulation (NBIA). Given the mitochondrial localization of the ...gene product the new NBIA subtype was designated mitochondrial membrane protein-associated neurodegeneration. Frequent features in the patients described so far included extrapyramidal signs and pyramidal tract involvement. Here, we report three
C19orf12
-mutant patients from two families presenting with predominant upper and lower motor neuron dysfunction mimicking amyotrophic lateral sclerosis with juvenile onset. While extrapyramidal signs were absent, all patients showed neuropsychological abnormalities with disinhibited or impulsive behavior. Optic atrophy was present in the simplex case. T2-weighted cranial MRI showed hypointensities suggestive of iron accumulation in the globi pallidi and the midbrain in all patients. Sequence analysis of
C19orf12
revealed a novel mutation, p.Gly66del, compound heterozygous with known mutations in all patients. These patients highlight that
C19orf12
defects should be considered as a differential diagnosis in patients with juvenile onset motor neuron diseases. Patients have to be examined carefully for neuropsychological abnormalities, optic neuropathy, and signs of brain iron accumulation in MRI.
The MitoP2 database (http://www.mitop.de) integrates information on mitochondrial proteins, their molecular functions and associated diseases. The central database features are manually annotated ...reference proteins localized or functionally associated with mitochondria supplied for yeast, human and mouse. MitoP2 enables (i) the identification of putative orthologous proteins between these species to study evolutionarily conserved functions and pathways; (ii) the integration of data from systematic genome-wide studies such as proteomics and deletion phenotype screening; (iii) the prediction of novel mitochondrial proteins using data integration and the assignment of evidence scores; and (iv) systematic searches that aim to find the genes that underlie common and rare mitochondrial diseases. The data and analysis files are referenced to data sources in PubMed and other online databases and can be easily downloaded. MitoP2 users can explore the relationship between mitochondrial dysfunctions and disease and utilize this information to conduct systems biology approaches on mitochondria.
Detailed clinical, neuroradiological, histological, biochemical, and genetic investigations were undertaken in a child suffering from Leigh syndrome. The clinical symptoms started at age five months ...and led to a severe progressive neurodegenerative disorder causing epilepsy, psychomotor retardation, and tetraspasticity. Biochemical measurement of skeletal muscle showed a severe decrease in mitochondrial complex II. Sequencing of SDHA revealed compound heterozygosity for a nonsense mutation in exon 4 (W119X) and a missense mutation in exon 3 (A83V), both absent in normal controls. In six additional patients—five with Leigh or Leigh-like syndrome and one with neuropathy and ataxia associated with isolated deficiency of complex II—mutations in SDHA were not detected, indicating genetic heterogeneity.
Mitochondrial disorders are associated with abnormalities of the oxidative phosphorylation (OXPHOS) system and cause significant morbidity and mortality in the population. The extensive clinical and ...genetic heterogeneity of these disorders due to a broad variety of mutations in several hundreds of candidate genes, encoded by either the mitochondrial DNA (mtDNA) or nuclear DNA (nDNA), impedes a straightforward genetic diagnosis. A new disease gene is presented here, identified in a single Kurdish patient born from consanguineous parents with neonatally fatal Leigh syndrome and complex I deficiency.
Using homozygosity mapping and subsequent positional candidate gene analysis, a total region of 255.8 Mb containing 136 possible mitochondrial genes was identified. A pathogenic mutation was found in the complex I subunit encoding the NDUFA9 gene, changing a highly conserved arginine at position 321 to proline. This is the first disease-causing mutation ever reported for NDUFA9. Complex I activity was restored in fibroblasts of the patient by lentiviral transduction with wild type but not mutant NDUFA9, confirming that the mutation causes the complex I deficiency and related disease.
The data show that homozygosity mapping and candidate gene analysis remain an efficient way to detect mutations even in small consanguineous pedigrees with OXPHOS deficiency, especially when the enzyme deficiency in fibroblasts allows appropriate candidate gene selection and functional complementation.
Background
Type 2 immune responses directed by Th2 cells and characterized by the signature cytokines IL4, IL5, and IL13 play major pathogenic roles in atopic diseases. Single nucleotide ...polymorphisms in the human Th2 cytokine locus in particular in a locus control region within the DNA repair gene RAD50, containing several RAD50 DNase1‐hypersensitive sites (RHS), have been robustly associated with atopic traits in genome‐wide association studies (GWAS). Functional variants in IL13 have been intensely studied, whereas no causative variants for the IL13‐independent RAD50 signal have been identified yet. This study aimed to characterize the functional impact of the atopy‐associated polymorphism rs2240032 located in the human RHS7 on cis‐regulatory activity and differential binding of transcription factors.
Methods
Differential transcription factor binding was analyzed by electrophoretic mobility shift assays (EMSAs) with Jurkat T‐cell nuclear extracts. Identification of differentially binding factors was performed using mass spectrometry (LC‐MS/MS). Reporter vector constructs carrying either the major or minor allele of rs2240032 were tested for regulating transcriptional activity in Jurkat and HeLa cells.
Results
The variant rs2240032 impacts transcriptional activity and allele‐specific binding of SMAD3, SP1, and additional putative protein complex partners. We further demonstrate that rs2240032 is located in an RHS7 subunit which itself encompasses repressor activity and might be important for the fine‐tuning of transcription regulation within this region.
Conclusion
The human RHS7 critically contributes to the regulation of gene transcription, and the common atopy‐associated polymorphism rs2240032 impacts transcriptional activity and transcription factor binding.
Loss of function of DJ‐1 (PARK7) is associated with autosomal recessive early‐onset Parkinson's disease (PD), one of the major age‐related neurological diseases. In this study, we extended former ...studies on DJ‐1 knockout mice by identifying subtle morphological and behavioural phenotypes. The DJ‐1 gene trap‐induced null mutants exhibit less dopamine‐producing neurons in the ventral tegmental area (VTA). They also exhibit slight changes in behaviour, i.e. diminished rearing behaviour and impairments in object recognition. Furthermore, we detected subtle phenotypes, which suggest that these animals compensate for the loss of DJ‐1. First, we found a significant upregulation of mitochondrial respiratory enzyme activities, a mechanism known to protect against oxidative stress. Second, a close to significant increase in c‐Jun N‐terminal kinase 1 phosphorylation in old DJ‐1‐deficient mice hints at a differential activation of neuronal cell survival pathways. Third, as no change in the density of tyrosine hydroxylase (TH)‐positive terminals in the striatum was observed, the remaining dopamine‐producing neurons likely compensate by increasing axonal sprouting. In summary, the present data suggest that DJ‐1 is implicated in major non‐motor symptoms of PD appearing in the early phases of the disease—such as subtle impairments in motivated behaviour and cognition—and that under basal conditions the loss of DJ‐1 is compensated
PDF
