👤 Divya Talwar

Hereditary Multiple Osteochondromas (HMO) is a rare, pediatric skeletal disorder characterized by osteochondromas that form along the growth plates. These benign tumors can cause skeletal deformities, joint dysfunction, chronic pain and other health problems. Most HMO patients are born with a heterozygous mutation in EXT1 or EXT2 that encode Golgi enzymes responsible for heparan sulfate synthesis. However, prior studies have established that these mutations alone are insufficient to trigger osteochondroma formation, but additional genetic changes are needed. Loss-of-heterozygosity (LOH) has been invoked in some cases, but the full genomic landscape of osteochondromas remains unclear. Here, we carried out a proof-of-principle study and asked whether gene variants occur in osteochondromas in addition to EXT mutations, whether the variants are shared by osteochondromas in same or different patients and what putative pathogenic roles they may have. A total of 8 tumors from 4 patients were subjected to whole exome sequencing (WES) along with saliva DNA from the 4 patients and 3 parents that was used as specific reference. WES identified over 1,600 somatic single nucleotide variants or insertion/deletions that were only partially shared amongst the tumors and were absent in the saliva DNA. Six genes were commonly mutated, including PABC1, TDG and ANKRD36. These genes exert action which could directly or indirectly influence chondrogenesis, the first differentiation step in osteochondroma formation. The study reveals that osteochondromas do possess gene variants distinguishing them in the same or different patients. These traits could modulate their tumorigenic character and add complexity to HMO pathogenesis. Clinical Significance: This study provides insights into the genomic landscape of osteochondromas, potentially leading to development of disease diagnostic and prognostic tools. Show less

Alzheimer's and Parkinson's disease are the most prevalent neurological diseases. Amyloid-β, tau, and α-synuclein proteins are known to be implicated in neurodegenerative disease (NDD). Elucidation of precise therapeutic targets remains a challenge. Therefore, the identification of interactomes of amyloid-β precursor protein (APP), microtubule-associated protein tau (MAPT), and α-synuclein (SNCA) proteins is of great interest, aimed at unraveling novel targets. An integrated analysis was employed to identify direct interactors as therapeutic targets, considering protein-protein interactions and subsequent network analysis. Further, it was proposed to identify hub proteins, intended targets, regulatory factors, disease-gene associations, functional enrichment analyses of the protein interactors interfered with gene ontologies and disease-driving pathways. Protein interactome centered on APP, MAPT, and SNCA identified the top hundred high-confidence protein-protein interactions that revealed BACE1, PSEN1, SORL1, GSK3B, CDK5, SNCAIP, PRKN, and APOE as physical and functional protein interactors. The top ten hub proteins were ranked based on multiple centrality measures and topological algorithms. Further, the integrated network of all three protein interactomes contained distinct nodes with edges. Interestingly, regulatory mechanisms have revealed possible regulatory modules, including cleavage, phosphorylation, and ubiquitination. Top interacting proteins were enriched in several ontology terms, such as regulation of neuronal apoptotic processes, amyloid beta fibril formation, and tau protein binding. Pathway analysis mapped the pathways of neurodegeneration-multiple disease, with a significant level of interacting proteins. Finally, the most comprehensive interactome associated with NDD provides insights into protein interactors, regulating the mechanisms of key proteins that can serve as novel therapeutic targets. Show less