Identification of novel compound heterozygous mutations in ACO2 in a patient with progressive cerebral and cerebellar atrophy

ConclusionThe marked reduction of aconitase activity in patient fibroblasts was due to the combination of decreased aconitase 2 amount and activity due to mutations. Reduced aconitase activity directly suppresses the TCA cycle, resulting in mitochondrial dysfunction, which may lead to symptoms similar to those observed in mitochondrial diseases.
Source: Molecular Genetics & Genomic Medicine - Category: Genetics & Stem Cells Authors: Tags: ORIGINAL ARTICLE Source Type: research

Related Links:

This article presents the original descriptions of some recent physics mechanisms (based on the thermodynamic, kinetic, and quantum tunnel effects) providing stable 2H/1H isotope fractionation, leading to the accumulation of particular isotopic forms in intra- or intercellular space, including the molecular effects of deuterium interaction with 18O/17O/16O, 15N/14N, 13C/12C, and other stable biogenic isotopes. These effects were observed mainly at the organelle (mitochondria) and cell levels. A new hypothesis for heavy nonradioactive isotope fractionation in living systems via neutron effect realization is discussed. The c...
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research
We present a sibling pair: one with cerebellar ataxia and one with vision loss and cognitive impairment in addition to ataxia. Neither shows evidence of leukoencephalopathy on MRI imaging. Exome sequencing revealed that both siblings are compound heterozygous forAARS2 variants (p.Phe131del and p.Ile328Met). Yeast complementation assays indicate that p.Phe131delAARS2 dramatically impairs gene function and that p.Ile328MetAARS2 is a hypomorphic allele. This work expands the phenotypic spectrum ofAARS2-associated disease to include ataxia without leukoencephalopathy.
Source: The Cerebellum - Category: Neurology Source Type: research
We present a sibling pair: one with cerebellar ataxia and one with vision loss and cognitive impairment in addition to ataxia. Neither shows evidence of leukoencephalopathy on MRI imaging. Exome sequencing revealed that both siblings are compound heterozygous for AARS2 variants (p.Phe131del and p.Ile328Met). Yeast complementation assays indicate that p.Phe131del AARS2 dramatically impairs gene function and that p.Ile328Met AARS2 is a hypomorphic allele. This work expands the phenotypic spectrum of AARS2-associated disease to include ataxia without leukoencephalopathy. PMID: 31705293 [PubMed - as supplied by publisher]
Source: Cerebellum - Category: Neuroscience Authors: Tags: Cerebellum Source Type: research
In conclusion, a polypharmacology approach of combining established, prolongevity drug inhibitors of specific nodes may be the most effective way to target the nutrient-sensing network to improve late-life health. Deletion of p38α in Neurons Slows Neural Stem Cell Decline and Loss of Cognitive Function in Mice https://www.fightaging.org/archives/2019/10/deletion-of-p38%ce%b1-in-neurons-slows-neural-stem-cell-decline-and-loss-of-cognitive-function-in-mice/ Researchers here provide evidence for p38α to be involved in the regulation of diminished neural stem cell activity with age. It is thought...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
ConclusionsWe describe a unique and novel cellular model that provides insight into the mitochondrial abnormalities present in DCMA and identifies SS-31 as a potential therapeutic for this devastating disease.
Source: Canadian Journal of Cardiology - Category: Cardiology Source Type: research
We report a case of genetic compensation in the fourth generation (F4) of slc25a46 knockout zebrafish mutant, in contrast to a penetrant disease phenotype in the first generation (F0) slc25a46 mosaic mutant (crispant), generated with CRISPR/Cas-9 technology. We show that F0 crispant phenotype is specific and rescuable. By performing mRNA sequencing, we define significant changes in slc25a46 F4 mutant ’s gene expression profile, which are nearly not present in F0 crispants. We find that among the top candidates for the phenotypic compensation anxa6 gene stands out as a functionally relevant player in mitochondrial dyn...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Danio rerio Source Type: research
In 2011 a 43-year-old man with retinitis pigmentosa, cerebellar ataxia, mild mental retardation and myopathy was seen in our outpatient clinic. He showed a limb girdle patter of weakness and CK persistently> 1.000 U/l. Due to the suggestive combination of symptoms and a likewise affected brother, he was considered to have a mitochondrial disorder. This was supported by some COX-negative fibres in a myopathic vastus lateralis biopsy, but genetic analysis failed to confirm this. He returned to our clinic in 2019 reporting that his retinal disease had been attributed to compound heterocygeous mutations in the MVK gene by h...
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
Chronic progressive ophthalmoplegia (CPEO) is a mitochondrial disease. It is part of a spectrum of mitochondrial DNA deletion disorders. In CPEO, by definition, the eye muscles are affected, causing eye movement deficits and ptosis. Phenotypes with further neurologic involvement are often described as CPEO-plus. Other phenotypes within the spectrum are well defined, such as Sensory Ataxia, Neuropathy, Dysarthria and Ophthalmoplegia (SANDO)-syndrome or Kearns-Sayre syndrome. In the future, well defined diagnostic criteria are essential for clinical trials.
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
The function of frataxin (FXN) has garnered great scientific interest since its depletion was linked to the incurable neurodegenerative disease Friedreich’s ataxia (FRDA). FXN has been shown to be necessary for iron-sulfur (Fe-S) cluster biosynthesis and proper mitochondrial function. The structural and functional core of the Fe-S cluster assembly complex...
Source: Proceedings of the National Academy of Sciences - Category: Science Authors: Tags: PNAS Plus Source Type: research
Abstract Friedreich ataxia is the most common of the hereditary ataxias. It is due to homozygous/compound heterozygous mutations in FXN. This gene encodes frataxin, a protein largely localized to mitochondria. In about 96% of affected individuals there is homozygosity for a GAA repeat expansion in intron 1 of the FXN gene. Studies of people with Friedreich ataxia and of animal and cell models, have provided much insight into the pathogenesis of this disorder. The expanded GAA repeat leads to transcriptional deficiency of the FXN gene. The consequent deficiency of frataxin protein leads to reduced iron-sulfur clust...
Source: Neurobiology of Disease - Category: Neurology Authors: Tags: Neurobiol Dis Source Type: research
More News: Ataxia | Genetics | Mitochondrial Disease | Opthalmology | Study