Phosphofurin acidic cluster sorting protein 1 (PACS1) pre-mRNA (PACS1 pre-mRNA)

Phosphofurin acidic cluster sorting protein 1 (PACS1) pre-mRNA is the primary transcript of the PACS1 gene, which encodes a cytosolic adapter protein essential for protein trafficking between the trans-Golgi network and endosomes (UniProt: Q6UX31). The PACS1 protein plays a critical role in embryonic development, particularly in the migration and specification of cranial neural crest cells (PubMed: 23042118). A specific recurrent de novo mutation in this transcript, c.607C>T (p.Arg203Trp), is the primary cause of Schuurs-Hoeijmakers syndrome (SHMS), a neurodevelopmental disorder characterized by intellectual disability and distinct facial features (OMIM: 615009). Because the mutation is thought to exert a dominant-negative or gain-of-function effect, the pre-mRNA and mature mRNA transcripts are targeted for therapeutic intervention. Current research focuses on using antisense oligonucleotides (ASOs) to selectively degrade the mutant transcript or modulate its splicing (PubMed: 33091363). This approach aims to restore normal cellular function by reducing the levels of the pathogenic protein while maintaining sufficient wild-type protein levels. Successful targeting of the PACS1 pre-mRNA represents a precision medicine strategy for treating SHMS and related neurodevelopmental conditions. Therapeutic development in this area also addresses the challenges of delivering genetic medicines to the central nervous system.

Other names

PACS-1 pre-mRNAPhosphofurin acidic cluster sorting protein 1 transcriptPACS1 mRNASchuurs-Hoeijmakers syndrome gene transcript

Allele-specific knockdown of mutant mRNA via RNase H-mediated degradation or splice modulation (PubMed: 33091363)