RESUMO
Rare diseases, defined by their low prevalence, present significant challenges, including delayed detection, expensive treatments, and limited research. This study delves into the genetic basis of two noteworthy rare diseases in Saudi Arabia: Phenylketonuria (PKU) and Spinal Muscular Atrophy (SMA). PKU, resulting from mutations in the phenylalanine hydroxylase (PAH) gene, exhibits geographical variability and impacts intellectual abilities. SMA, characterized by motor neuron loss, is linked to mutations in the survival of motor neuron 1 (SMN1) gene. Recognizing the importance of unveiling signature genomics in rare diseases, we conducted a quantitative study on PAH and SMN1 proteins of multiple organisms by employing various quantitative techniques to assess genetic variations. The derived signature-genomics contributes to a deeper understanding of these critical genes, paving the way for enhanced diagnostics for disorders associated with PAH and SMN1.
Assuntos
Genômica , Atrofia Muscular Espinal , Fenilalanina Hidroxilase , Fenilcetonúrias , Doenças Raras , Proteína 1 de Sobrevivência do Neurônio Motor , Atrofia Muscular Espinal/genética , Fenilcetonúrias/genética , Humanos , Fenilalanina Hidroxilase/genética , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Genômica/métodos , Doenças Raras/genética , Mutação , Arábia Saudita/epidemiologiaRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the rapidly evolving RNA virus behind the COVID-19 pandemic, has spawned numerous variants since its 2019 emergence. The multifunctional Nonstructural protein 14 (NSP14) enzyme, possessing exonuclease and messenger RNA (mRNA) capping capabilities, serves as a key player. Notably, single and co-occurring mutations within NSP14 significantly influence replication fidelity and drive variant diversification. This study comprehensively examines 120 co-mutations, 68 unique mutations, and 160 conserved residues across NSP14 homologs, shedding light on their implications for phylogenetic patterns, pathogenicity, and residue interactions. Quantitative physicochemical analysis categorizes 3953 NSP14 variants into three clusters, revealing genetic diversity. This research underscoresthe dynamic nature of SARS-CoV-2 evolution, primarily governed by NSP14 mutations. Understanding these genetic dynamics provides valuable insights for therapeutic and vaccine development.
Assuntos
COVID-19 , Exorribonucleases , SARS-CoV-2 , Proteínas não Estruturais Virais , Humanos , COVID-19/genética , Exorribonucleases/química , Exorribonucleases/genética , Exorribonucleases/metabolismo , Mutação/genética , Pandemias , Filogenia , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Replicação Viral/genética , Proteínas não Estruturais Virais/metabolismoRESUMO
The number one cause of human fetal death are defects in heart development. Because the human embryonic heart is inaccessible and the impacts of mutations, drugs, and environmental factors on the specialized functions of different heart compartments are not captured by in vitro models, determining the underlying causes is difficult. Here, we established a human cardioid platform that recapitulates the development of all major embryonic heart compartments, including right and left ventricles, atria, outflow tract, and atrioventricular canal. By leveraging 2D and 3D differentiation, we efficiently generated progenitor subsets with distinct first, anterior, and posterior second heart field identities. This advance enabled the reproducible generation of cardioids with compartment-specific in vivo-like gene expression profiles, morphologies, and functions. We used this platform to unravel the ontogeny of signal and contraction propagation between interacting heart chambers and dissect how mutations, teratogens, and drugs cause compartment-specific defects in the developing human heart.
