Genes · 2025
RNA Polymerase I Dysfunction Underlying Craniofacial Syndromes: Integrated Genetic Analysis Reveals Parallels to 22q11.2 Deletion Syndrome.
СтатьяКлинический случайНазвание и аннотация: Перевод в очереди
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Silvey Spencer, Lovell Scott, Butler Merlin G
Аннотация
BACKGROUND/OBJECTIVE: POLR1A and related gene variants cause craniofacial and developmental syndromes, including Acrofacial Dysostosis-Cincinnati, Treacher-Collins types 2-4, and TWIST1-associated disorders. Using a patient case integrated with molecular analyses, we aimed to clarify shared pathogenic mechanisms and propose these conditions as part of a spectrum of RNA polymerase I (Pol I)-related ribosomopathies.
METHODS: A patient with a heterozygous POLR1A variant underwent clinical evaluation. Findings were integrated with a literature review of craniofacial syndromes to identify overlapping fea tures. Protein-protein and gene-gene interactions were analyzed with STRING and Pathway Commons, a structural modeling of POLR1A assessed the mutation's impact.
RESULTS: The patient exhibited features overlapping with Sweeney-Cox, Saethre-Cox, Robinow-Sorauf, and Treacher-Collins types 2-4, supporting a shared spectrum. Computational analyses identified POLR1A-associated partners and pathways converging on Pol I function, ribosomal biogenesis, and nucleolar processes. Structural modeling of the Met496Ile variant suggested disruption of DNA binding and polymerase activity, linking molecular dysfunction to the clinical phenotype.
CONCLUSION: Significant clinical and genetic overlap exists among Saethre-Chotzen, Sweeney-Cox, Treacher-Collins types 2-4, and Acrofacial Dysostosis-Cincinnati. POLR1A and related Pol I subunits provide a mechanistic basis through impaired nucleolar organization and rRNA transcription, contributing to abnormal craniofacial development. Integrative protein, gene, and structural analyses support classifying these syndromes as Pol I-related ribosomopathies, with implications for diagnosis, counseling, and future mechanistic or therapeutic studies.
METHODS: A patient with a heterozygous POLR1A variant underwent clinical evaluation. Findings were integrated with a literature review of craniofacial syndromes to identify overlapping fea tures. Protein-protein and gene-gene interactions were analyzed with STRING and Pathway Commons, a structural modeling of POLR1A assessed the mutation's impact.
RESULTS: The patient exhibited features overlapping with Sweeney-Cox, Saethre-Cox, Robinow-Sorauf, and Treacher-Collins types 2-4, supporting a shared spectrum. Computational analyses identified POLR1A-associated partners and pathways converging on Pol I function, ribosomal biogenesis, and nucleolar processes. Structural modeling of the Met496Ile variant suggested disruption of DNA binding and polymerase activity, linking molecular dysfunction to the clinical phenotype.
CONCLUSION: Significant clinical and genetic overlap exists among Saethre-Chotzen, Sweeney-Cox, Treacher-Collins types 2-4, and Acrofacial Dysostosis-Cincinnati. POLR1A and related Pol I subunits provide a mechanistic basis through impaired nucleolar organization and rRNA transcription, contributing to abnormal craniofacial development. Integrative protein, gene, and structural analyses support classifying these syndromes as Pol I-related ribosomopathies, with implications for diagnosis, counseling, and future mechanistic or therapeutic studies.