Although Down syndrome (DS) is the most frequent human chromosomal disorder and it causes mainly intellectual disability, its clinical presentation is complex and variable.
We aimed to analyze and ...compare the transcriptome disruption in several brain areas from individuals with DS and euploid controls as a new approach to consider a global systemic differential disruption of gene expression beyond chromosome 21.
We used data from a DNA microarray experiment with ID GSE59630 previously deposited in the GEO DataSet of NCBI database. The array contained log2 values of 17,537 human genes expressed in several aeras of the human brain. We calculated the differential gene expression (Z-ratio) of all genes.
We found several differences in gene expression along the DS brain transcriptome, not only in the genes located at chromosome 21 but in other chromosomes. Moreover, we registered the lowest Z-ratio correlation between the age ranks of 16-22 weeks of gestation and 39-42 years (R
= 0.06) and the highest Z-ratio correlation between the age ranks of 30-39 years and 40-42 years (R
= 0.89). The analysis per brain areas showed that the hippocampus and the cerebellar cortex had the most different gene expression pattern when compared to the brain as a whole.
Our results support the hypothesis of a systemic imbalance of brain protein homeostasis, or proteostasis network of cognitive and neuroplasticity process, as new model to explain the important effect on the neurophenotype of trisomy that occur not only in the loci of chromosome 21 but also in genes located in other chromosomes.
DNA methylation and histone posttranslational modifications are epigenetics processes that contribute to neurophenotype of Down Syndrome (DS). Previous reports present strong evidence that nonhistone ...high-mobility-group N proteins (HMGN) are epigenetic regulators. They play important functions in various process to maintain homeostasis in the brain. We aimed to analyze the differential expression of five human HMGN genes in some brain structures and age ranks from DS postmortem brain samples.
We performed a computational analysis of the expression of human HMGN from the data of a DNA microarray experiment (GEO database ID GSE59630). Using the transformed log2 data, we analyzed the differential expression of five HMGN genes in several brain areas associated with cognition in patients with DS. Moreover, using information from different genome databases, we explored the co-expression and protein interactions of HMNGs with the histones of nucleosome core particle and linker H1 histone.
We registered that HMGN1 and HMGN5 were significantly overexpressed in the hippocampus and areas of prefrontal cortex including DFC, OFC, and VFC of DS patients. Age-rank comparisons between euploid control and DS individuals showed that HMGN2 and HMGN4 were overexpressed in the DS brain at 16 to 22 gestation weeks. From the BioGRID database, we registered high interaction scores of HMGN2 and HMGN4 with Hist1H1A and Hist1H3A.
Overall, our results give strong evidence to propose that DS would be an epigenetics-based aneuploidy. Remodeling brain chromatin by HMGN1 and HMGN5 would be an essential pathway in the modification of brain homeostasis in DS.
Sexual dimorphism in the Laysan albatross (
) on Guadalupe Island was evaluated during the breeding seasons of 2015-2018 by measuring and comparing 10 morphological attributes: cranial length, bill ...length, nostril length, cranial width, bill height, bill width, tarsus length, closed wing length, opened wing length, and wingspan length in reproductive adults (
= 135). Males were larger than females across all traits (Student's
-test,
< 0.05,
< 0.05). We created a logistic model using stepwise regression to predict sex based on morphological variables. This model indicated four significant morphological predictor variables (
< 0.05) and was able to successfully predict the sex of
individuals in more than 90% of the cases. Based on these predictor variables, a web app was developed to determine the sex of the Laysan albatross in the field, providing a non-invasive method for rapid data collection that reduces costs and handling times while improving conservation efforts. We tracked Laysan albatross (
= 36) during breeding seasons and found no significant differences between females and males for either trip length (GLMM, F = 0.017, DF = 1, 1,
= 0.917 > 0.05) or maximum trip distance (GLMM, F = 0.374, DF = 1, 1,
= 0.651 > 0.05). Our results suggest that both sexes show a strong preference to travel to highly productive coastal waters northeast of the breeding colony that are influenced by the California Current. The present research will serve to establish a baseline to protect this species on Guadalupe Island and highlights the importance of understanding sexual dimorphism in at-risk seabird species.
•An hiPSC line was generated from a compound heterozygous patient in TK2 gene.•Pluripotency of new hiPSC line was evaluated and confirmed by specific parameters.•This hiPSC line will be useful for ...testing therapies in cell types normally affected in patients who suffer from TK2 deficiency.
Autosomal recessive mutations in Thymidine kinase 2 (TK2) gene cause depletion and multiple deletions in mtDNA which normally lead to fatal and progressive neuromyopathy in infants and children. We have generated an induced pluripotent stem cell (iPSC) line by reprogramming fibroblasts derived from a patient carrying TK2 mutations. New iPSC line pluripotency was evaluated by verifying the expression of pluripotency-related genes and the in vitro differentiation into the three germ layers. This human-derived model will be useful for studying the pathogenic mechanisms triggered by these mutations and for testing therapies in cell types normally affected in patients.
Most patients suffering from Leber hereditary optic neuropathy carry one of the three classic pathologic mutations, but not all individuals with these genetic alterations develop the disease. There ...are different risk factors that modify the penetrance of these mutations. The remaining patients carry one of a set of very rare genetic variants and, it appears that, some of the risk factors that modify the penetrance of the classical pathologic mutations may also affect the phenotype of these other rare mutations.
We describe a large family including 95 maternally related individuals, showing 30 patients with Leber hereditary optic neuropathy. The mutation responsible for the phenotype is a novel transition, m.3734A > G, in the mitochondrial gene encoding the ND1 subunit of respiratory complex I. Molecular-genetic, biochemical and cellular studies corroborate the pathogenicity of this genetic change.
With the study of this family, we confirm that, also for this very rare mutation, sex and age are important factors modifying penetrance. Moreover, this pedigree offers an excellent opportunity to search for other genetic or environmental factors that additionally contribute to modify penetrance.
Can folic acid have a role in mitochondrial disorders? Ormazabal, Aida; Casado, Mercedes; Molero-Luis, Marta ...
Drug discovery today,
November 2015, 2015-Nov, 2015-11-00, 20151101, Letnik:
20, Številka:
11
Journal Article
Recenzirano
•Folate metabolism in the cell is highly compartmentalized.•There are evidences of the importance of folate regarding mitochondrial function.•Cerebral folate deficiency is frequent in certain ...mitochondrial disorders.•Folate treatment has positive effects in patients with mitochondrial DNA deletions.
Cellular folate metabolism is highly compartmentalized, with mitochondria folate transport and metabolism being distinct from the well-known cytosolic folate metabolism. There is evidence supporting the association between low folate status and mitochondrial DNA (mtDNA) instability, and cerebral folate deficiency is relatively frequent in mitochondrial disorders. Furthermore, folinic acid supplementation has been reported to be beneficial not only in some patients with mitochondrial disease, but also in patients with relatively common diseases where folate deficiency might be an important pathophysiological factor. In this review, we focus on the evidence that supports the potential involvement of impaired folate metabolism in the pathophysiology of mitochondrial disorders.
Mitochondrial oxidative phosphorylation disorders are extremely heterogeneous conditions. Their clinical and genetic variability makes the identification of reliable and specific biomarkers very ...challenging. Until now, only a few studies have focused on the effect of a defective oxidative phosphorylation functioning on the cell's secretome, although it could be a promising approach for the identification and pre-selection of potential circulating biomarkers for mitochondrial diseases. Here, we review the insights obtained from secretome studies with regard to oxidative phosphorylation dysfunction, and the biomarkers that appear, so far, to be promising to identify mitochondrial diseases. We propose two new biomarkers to be taken into account in future diagnostic trials.
Thymidine kinase (TK2) deficiency causes mitochondrial DNA depletion syndrome. We aimed to report the clinical, biochemical, genetic, histopathological, and ultrastructural features of a cohort of ...paediatric patients with TK2 deficiency. Mitochondrial DNA was isolated from muscle biopsies to assess depletions and deletions. The TK2 genes were sequenced using Sanger sequencing from genomic DNA. All muscle biopsies presented ragged red fibres (RRFs), and the prevalence was greater in younger ages, along with an increase in succinate dehydrogenase (SDH) activity and cytochrome c oxidase (COX)-negative fibres. An endomysial inflammatory infiltrate was observed in younger patients and was accompanied by an overexpression of major histocompatibility complex type I (MHC I). The immunofluorescence study for complex I and IV showed a greater number of fibres than those that were visualized by COX staining. In the ultrastructural analysis, we found three major types of mitochondrial alterations, consisting of concentrically arranged lamellar cristae, electrodense granules, and intramitochondrial vacuoles. The pathological features in the muscle showed substantial differences in the youngest patients when compared with those that had a later onset of the disease. Additional ultrastructural features are described in the muscle biopsy, such as sarcomeric de-structuration in the youngest patients with a more severe phenotype.
To perform a deep phenotype characterisation in a pedigree of 3 siblings with Leigh syndrome and compound heterozygous NDUFAF6 mutations.
A multi-gene panel of childhood-onset basal ganglia ...neurodegeneration inherited conditions was analysed followed by functional studies in fibroblasts.
Three siblings developed gait dystonia in infancy followed by rapid progression to generalised dystonia and psychomotor regression. Brain magnetic resonance showed symmetric and bilateral cytotoxic lesions in the putamen and proliferation of the lenticular-striate arteries, latter spreading to the caudate and progressing to cavitation and volume loss. We identified a frameshift novel change (c.554_558delTTCTT; p.Tyr187AsnfsTer65) and a pathogenic missense change (c.371T>C; p.Ile124Thr) in the NDUFAF6 gene, which segregated with an autosomal recessive inheritance within the family. Patient mutations were associated with the absence of the NDUFAF6 protein and reduced activity and assembly of mature complex I in fibroblasts. By functional complementation assay, the mutant phenotype was rescued by the canonical version of the NDUFAF6. A literature review of 14 NDUFAF6 patients showed a consistent phenotype of an early childhood insidious onset neurological regression with prominent dystonia associated with basal ganglia degeneration and long survival.
NDUFAF6-related Leigh syndrome is a relevant cause of childhood onset dystonia and isolated bilateral striatal necrosis. By genetic complementation, we could demonstrate the pathogenicity of novel genetic variants in NDUFAF6.
Pearson syndrome is a rare multisystem disease caused by single large-scale mitochondrial DNA deletions (SLSMDs). The syndrome presents early in infancy and is mainly characterised by refractory ...sideroblastic anaemia. Prognosis is poor and treatment is supportive, thus the development of new models for the study of Pearson syndrome and new therapy strategies is essential. In this work, we report three different cell models carrying an SLMSD: fibroblasts, transmitochondrial cybrids and induced pluripotent stem cells (iPSCs). All studied models exhibited an aberrant mitochondrial ultrastructure and defective oxidative phosphorylation system function, showing a decrease in different parameters, such as mitochondrial ATP, respiratory complex IV activity and quantity or oxygen consumption. Despite this, iPSCs harbouring 'common deletion' were able to differentiate into three germ layers. Additionally, cybrid clones only showed mitochondrial dysfunction when heteroplasmy level reached 70%. Some differences observed among models may depend on their metabolic profile; therefore, we consider that these three models are useful for the in vitro study of Pearson syndrome, as well as for testing new specific therapies. This article has an associated First Person interview with the first author of the paper.
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