ArticleScientific reports2019
A network biology approach to unraveling inherited axonopathies.
Article in Scientific reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 21 citations in OpenAlex.
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- Integrative network analysis interweaves the missing links in cardiomyopathy diseasome.Scientific reports · 2022Article
- Biological networks and complexity in early-onset motor neuron diseases.Frontiers in neurology · 2022Article
- Integrating protein networks and machine learning for disease stratification in the Hereditary Spastic Paraplegias.iScience · 2021Article
- The Role of Protein Adduction in Toxic Neuropathies of Exogenous and Endogenous Origin.Toxics · 2021Review
- Network and Evolutionary Analysis of Human Epigenetic Regulators to Unravel Disease Associations.Genes · 2020Article
- SAlign-a structure aware method for global PPI network alignment.BMC bioinformatics · 2020Article
- Neuroprotein Targets of γ-Diketone Metabolites of Aliphatic and Aromatic Solvents That Induce Central-Peripheral Axonopathy.Toxicologic pathology · 2020Review
- Overlapping spectrums: The clinicogenetic commonalities between Charcot-Marie-Tooth and other neurodegenerative diseases.Brain research · 2020Review
- Perspectives on the Genomics of HSP Beyond Mendelian Inheritance.Frontiers in neurology · 2018Review
- Genetic Spectrum of Inherited Neuropathies in India.Annals of Indian Academy of NeurologyArticle
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Inherited axonopathies represent a spectrum of disorders unified by the common pathological mechanism of length-dependent axonal degeneration. Progressive axonal degeneration can lead to both Charcot-Marie-Tooth type 2 (CMT2) and Hereditary Spastic Paraplegia (HSP) depending on the affected neurons: peripheral motor and sensory nerves or central nervous system axons of the corticospinal tract and dorsal columns, respectively. Inherited axonopathies display an extreme degree of genetic heterogeneity of Mendelian high-penetrance genes. High locus heterogeneity is potentially advantageous to deciphering disease etiology by providing avenues to explore biological pathways in an unbiased fashion. Here, we investigate 'gene modules' in inherited axonopathies through a network-based analysis of the Human Integrated Protein-Protein Interaction rEference (HIPPIE) database. We demonstrate that CMT2 and HSP disease proteins are significantly more connected than randomly expected. We define these connected disease proteins as 'proto-modules' and show the topological relationship of these proto-modules by evaluating their overlap through a shortest-path based measurement. In particular, we observe that the CMT2 and HSP proto-modules significantly overlapped, demonstrating a shared genetic etiology. Comparison of both modules with other diseases revealed an overlapping relationship between HSP and hereditary ataxia and between CMT2 + HSP and hereditary ataxia. We then use the DIseAse Module Detection (DIAMOnD) algorithm to expand the proto-modules into comprehensive disease modules. Analysis of disease modules thus obtained reveals an enrichment of ribosomal proteins and pathways likely central to inherited axonopathy pathogenesis, including protein processing in the endoplasmic reticulum, spliceosome, and mRNA processing. Furthermore, we determine pathways specific to each axonopathy by analyzing the difference of the axonopathy modules. CMT2-specific pathways include glycolysis and gluconeogenesis-related processes, while HSP-specific pathways include processes involved in viral infection response. Unbiased characterization of inherited axonopathy disease modules will provide novel candidate disease genes, improve interpretation of candidate genes identified through patient data, and guide therapy development.
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