HADHA and HADHB gene associated phenotypes - Identification of rare variants in a patient cohort by Next Generation Sequencing

Diebold, Isabel; Schön, Ulrike; Horvath, Rita; Schwartz, Oliver; Holinski‐Feder, Elke; Kölbel, Heike; Schöser, Benedikt

doi:10.1016/j.mcp.2019.01.003

Cited by 21 publications

(22 citation statements)

References 26 publications

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“…(e) Recurrent rhabdomyolyses, myoglobinuria, neuropathy, distal muscle atrophy, exercice intolerance, Neuropathy (axonal, sensorimotor), distal muscle atrophy, elevated creatine kinase 23 ;…”

Section: Resultsmentioning

confidence: 99%

Expanding the genotype–phenotype correlation of childhood sensory polyneuropathy of genetic origin

Chakravorty

Logan

Elson

et al. 2020

Sci Rep

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Pure sensory polyneuropathy of genetic origin is rare in childhood and hence important to document the clinical and genetic etiologies from single or multi-center studies. This study focuses on a retrospective chart-review of neurological examinations and genetic and electrodiagnostic data of confirmed sensory polyneuropathy in subjects at a tertiary-care Children’s Hospital from 2013 to 2019. Twenty subjects were identified and included. Neurological examination and electrodiagnostic testing showed gait-difficulties, absent tendon reflexes, decreased joint-position, positive Romberg’s test and large fiber sensory polyneuropathy on sensory nerve conduction studies in all patients associated with lower-extremity spasticity (6), cardiac abnormalities or cardiomyopathy (5), developmental delay (4), scoliosis (3), epilepsy (3) and hearing-difficulties (2). Confirmation of genetic diagnosis in correlation with clinical presentation was obtained in all cases (COX20 n = 2, HADHA n = 2, POLG n = 1, FXN n = 4, ATXN2 n = 3, ATM n = 3, GAN n = 2, SPG7 n = 1, ZFYVE26 n = 1, FH n = 1). Our single-center study shows genetic sensory polyneuropathies associated with progressive neurodegenerative disorders such as mitochondrial ataxia, Friedreich ataxia, spinocerebellar ataxia type 2, ataxia telangiectasia, spastic paraplegia, giant axonal neuropathy, and fumarate hydratase deficiency. We also present our cohort data in light of clinical features reported for each gene-specific disease subtype in the literature and highlight the importance of genetic testing in the relevant clinical context of electrophysiological findings of peripheral sensory polyneuropathy.

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Section: Resultsmentioning

confidence: 99%

Expanding the genotype–phenotype correlation of childhood sensory polyneuropathy of genetic origin

Chakravorty

Logan

Elson

et al. 2020

Sci Rep

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“…As a paralog of Acox1, Acox3 contributes significantly to peroxisomal branched-chain fatty acid beta-oxidation [33]. Hadha and Hadhb respectively encode the alpha and beta subunits of the mitochondrial trifunctional protein, which catalyzes the last three steps of mitochondrial beta-oxidation of long-chain fatty acids [34]. Our data indicate that Dicer gene deletion significantly reduces Hadhb, but not Hadha, expression.…”

Section: Discussionmentioning

confidence: 96%

RNAase III-Type Enzyme Dicer Regulates Mitochondrial Fatty Acid Oxidative Metabolism in Cardiac Mesenchymal Stem Cells

Jin

Shen

et al. 2019

IJMS

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Cardiac mesenchymal stem cells (C-MSC) play a key role in maintaining normal cardiac function under physiological and pathological conditions. Glycolysis and mitochondrial oxidative phosphorylation predominately account for energy production in C-MSC. Dicer, a ribonuclease III endoribonuclease, plays a critical role in the control of microRNA maturation in C-MSC, but its role in regulating C-MSC energy metabolism is largely unknown. In this study, we found that Dicer knockout led to concurrent increase in both cell proliferation and apoptosis in C-MSC compared to Dicer floxed C-MSC. We analyzed mitochondrial oxidative phosphorylation by quantifying cellular oxygen consumption rate (OCR), and glycolysis by quantifying the extracellular acidification rate (ECAR), in C-MSC with/without Dicer gene deletion. Dicer gene deletion significantly reduced mitochondrial oxidative phosphorylation while increasing glycolysis in C-MSC. Additionally, Dicer gene deletion selectively reduced the expression of β-oxidation genes without affecting the expression of genes involved in the tricarboxylic acid (TCA) cycle or electron transport chain (ETC). Finally, Dicer gene deletion reduced the copy number of mitochondrially encoded 1,4-Dihydronicotinamide adenine dinucleotide (NADH): ubiquinone oxidoreductase core subunit 6 (MT-ND6), a mitochondrial-encoded gene, in C-MSC. In conclusion, Dicer gene deletion induced a metabolic shift from oxidative metabolism to aerobic glycolysis in C-MSC, suggesting that Dicer functions as a metabolic switch in C-MSC, which in turn may regulate proliferation and environmental adaptation.

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“…The Hydroxyacyl-CoA Dehydrogenase Trifunctional Multienzyme Complex Subunit Beta gene was downregulated in the lipolysis process. The HADHB gene is a protein-encoding gene with pathways such as beta-oxidation of mitochondrial fatty acids and biosynthesis of glycerophospholipids ( Diebold et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Omics Multi-Layers Networks Provide Novel Mechanistic and Functional Insights Into Fat Storage and Lipid Metabolism in Poultry

et al. 2021

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Fatty acid metabolism in poultry has a major impact on production and disease resistance traits. According to the high rate of interactions between lipid metabolism and its regulating properties, a holistic approach is necessary. To study omics multilayers of adipose tissue and identification of genes and miRNAs involved in fat metabolism, storage and endocrine signaling pathways in two groups of broiler chickens with high and low abdominal fat, as well as high-throughput techniques, were used. The gene–miRNA interacting bipartite and metabolic-signaling networks were reconstructed using their interactions. In the analysis of microarray and RNA-Seq data, 1,835 genes were detected by comparing the identified genes with significant expression differences (p.adjust < 0.01, fold change ≥ 2 and ≤ −2). Then, by comparing between different data sets, 34 genes and 19 miRNAs were detected as common and main nodes. A literature mining approach was used, and seven genes were identified and added to the common gene set. Module finding revealed three important and functional modules, which were involved in the peroxisome proliferator-activated receptor (PPAR) signaling pathway, biosynthesis of unsaturated fatty acids, Alzheimer’s disease metabolic pathway, adipocytokine, insulin, PI3K–Akt, mTOR, and AMPK signaling pathway. This approach revealed a new insight to better understand the biological processes associated with adipose tissue.

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HADHA and HADHB gene associated phenotypes - Identification of rare variants in a patient cohort by Next Generation Sequencing

Cited by 21 publications

References 26 publications

Expanding the genotype–phenotype correlation of childhood sensory polyneuropathy of genetic origin

Expanding the genotype–phenotype correlation of childhood sensory polyneuropathy of genetic origin

RNAase III-Type Enzyme Dicer Regulates Mitochondrial Fatty Acid Oxidative Metabolism in Cardiac Mesenchymal Stem Cells

Omics Multi-Layers Networks Provide Novel Mechanistic and Functional Insights Into Fat Storage and Lipid Metabolism in Poultry

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