The human genome contains hundreds of thousands of short open reading frames (sORFs), yet their translational products, hereafter referred to as sORF-encoded microproteins (also historically termed micropeptides), have long remained overlooked in conventional genome annotation. Increasing evidence demonstrates that these molecules play critical regulatory roles in human physiology and disease. This narrative review summarizes current knowledge regarding the classification, discovery, translational regulation, and biological significance of sORF-encoded microproteins. Their expression is tightly controlled by epigenetic mechanisms, including DNA methylation, Polycomb-mediated H3K27 trimethylation, and bivalent histone modifications, as well as epitranscriptomic regulation through N6-methyladenosine-mediated translation. Key microproteins such as Humanin, MOTS-c, Myoregulin, DWORF, HOXB-AS3-p, Mitoregulin, and CASIMO1 illustrate the diverse roles of sORF-derived peptides in cardiometabolic disease, neurodegeneration, and cancer. The review also highlights emerging therapeutic strategies, including epigenome editing, peptide replacement, and immunopeptidome-based neoantigen targeting. Collectively, the sORF-encoded microproteome represents an epigenetically integrated and functionally significant regulatory layer of the human proteome with major implications for fundamental biology and precision medicine.
Ayman M. Mustafa, Rebaz M. Ali, S. Omar et al.· Epigenomics· 0 citations
BACKGROUND
Mitochondrial Contact Site and Cristae Organizing System (MICOS13)- related combined oxidative phosphorylation deficiency 37 is a rare autosomal recessive disorder caused by disruption of mitochondrial structure and function, leading to early-onset multisystem disease. Case report: A genetically confirmed case is described in a 5-month-old female infant born to consanguineous Iraqi parents, presenting with hypotonia, developmental delay, feeding difficulties, laryngomalacia, and recurrent cyanotic episodes. Clinical findings included diminished reflexes and a small atrial septal defect, while laboratory tests revealed hypoalbuminaemia and mild coagulopathy. Whole-exome sequencing identified a homozygous MICOS13 splice-site variant (c.260-2A >G). Despite supportive care, progressive respiratory failure developed, resulting in death at 5months. Review of 13 reported cases demonstrates consistent early onset, universal hepatic and neurological involvement, frequent respiratory compromise, and, among reported cases, uniformly fatal outcomes. Most identified variants are loss-of-function, predominantly frameshift, with no missense variants reported to date.
CONCLUSION
The present report adds a genetically confirmed case and reinforces the value of considering MICOS13 deficiency in consanguineous infants with early encephalopathy and hepatic dysfunction.
K. Hamad, Sadraldin-Ali Braim, Dyari Q. Hamad et al.· Fetal and Pediatric Patholog...· 0 citations
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