Deleterious, mostly de novo, mutations in the lamin A (LMNA) gene cause spatio‐functional nuclear abnormalities that result in several laminopathy‐associated progeroid conditions. In this study, exome sequencing in a sixteen‐year‐old male with manifestations of premature aging led to the identification of a mutation, c.784G>A, in LMNA, resulting in a missense protein variant, p.Glu262Lys (E262K), that aggregates in nucleoplasm. While bioinformatic analyses reveal the instability and pathogenicity of LMNAE262K, local unfolding of the mutation‐harboring helical region drives the structural collapse of LMNAE262K into aggregates. The E262K mutation also disrupts SUMOylation of lysine residues by preventing UBE2I binding to LMNAE262K, thereby reducing LMNAE262K degradation, aggregated LMNAE262K sequesters nuclear chaperones, proteasomal proteins, and DNA repair proteins. Consequently, aggregates of LMNAE262K disrupt nuclear proteostasis and DNA repair response. Thus, we report a structure–function association of mutant LMNAE262K with toxicity, which is consistent with the concept that loss of nuclear proteostasis causes early aging in laminopathies.
Retinoblastoma is an embryonic intraocular tumor arising in the retina of the eye. It is a dangerous tumor that can damage the eye and its surrounding components. Chromosome 13q14.1-14.2 is the cytogenetic location of the RB1 gene. As a result, early identification of Retinoblastoma in children is essential. Over the last few decades, Retinoblastoma treatment has improved with the goal of not only saving life and the eye but also optimizing residual vision. In oncology, machine learning approaches used to predict cancer patient treatment outcomes include data collection and preprocessing, text mining of clinical literature, and constructing prediction models. This paper discusses recent advances in the management of Retinoblastoma, as well as data preparation and model construction for identifying patterns between Retinoblastoma clinical factors and predicting therapy success using machine learning.
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