Eukaryotic translation is a complex process and is principally regulated at the initiation stage. Alterations in this process can lead to diseased states. In this review, we outline the cap-dependent translation initiation process and discuss the association of dysregulated initiation factors with rare disease conditions. We reviewed 16 rare diseases with defects in translation initiation factors. The ternary complex formation, especially eIF2 activity and mRNA activation, specifically eIF4F complex formation are the most affected steps. Most of the rare diseases affected neuronal tissue followed by endocrine system, suggesting the importance of immediate and direct regulation of protein synthesis in these tissues. Even though the defects in translation initiation factors have been associated with various rare diseases, the precise molecular pathogenesis is not completely understood for all the factors. Understanding the molecular regulation of these initiation factors in different tissues and conditions will enable us to identify diagnostic and prognostic markers for rare diseases and explore new therapeutic interventions.

Rare and undiagnosed diseases tend to be diverse, misdiagnosed, and difficult to diagnose. In some cases, the disease is progressive and life-threatening. Yet, to date, an estimated 95% of rare diseases have no approved therapy. Therefore, rare and undiagnosed diseases are considered the ultimate challenges for understanding human diseases. Here, we review the research progress, research frontiers, and important scientific issues related to rare and undiagnosed diseases. We mainly focus on five topics: (1) the identification and functional analysis of disease-causing genes; (2) the construction of cells, organoids, and animal models for mechanism validation; (3) subtyping and diagnosis; (4) treatment and drug screening based on causative genes and mutations; and (5) new technologies and methods for studying rare and undiagnosed diseases. In this review, we briefly update and discuss the pathogenic mechanisms and precision medicine for rare and undiagnosed diseases.

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Sofia
Journal Co-ordinator
Journal of Rare Disorders: Diagnosis & Therapy