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The role of PACS2 and pacs2 in ocular development

Laboratory Genetics and Genomics
  • Primary Categories:
    • Laboratory Genetics
  • Secondary Categories:
    • Laboratory Genetics
Introduction:
Pathogenic variants in phosphofurin acid cluster sorting protein 2 (PACS2) have been associated with developmental and epileptic encephalopathy (DEE), developmental delays and facial anomalies. Recently, a patient with coloboma was found to have a heterozygous, recurrent pathogenic variant, c.625G>A p.Glu209Lys, in PACS2. This finding supports the hypothesis that PACS2 is associated with developmental eye defects, as the protein forms a complex with associated the proteins PACS1 and WDR37 that are associated with ocular coloboma. Eye phenotypes have been reported to be comparatively rare in patients with pathogenic variants in PACS2 but have not recently been reviewed. Zebrafish demonstrate excellent conservation with human eye development and have long been a model for human ocular disease. As a model organism, they have several advantages for the study of ocular development due to their quick maturation.

Methods:
We performed a literature review of 59 previously reported patients with PACS2-associated disease, as well as patients with chromosomal deletions including PACS2, to comprehensively describe the disease phenotype, including ocular findings. We used CRISPR/Cas9 to create two zebrafish lines with frameshift mutations in the 6th exon of pacs2, upstream to the site of the equivalent p.E208K variant and autoregulatory region of the gene. We generated pacs2-/- larvae and characterized their phenotype and development using morphometric analysis, immunohistochemistry and qRT-PCR.

Results:
Our literature review showed novel ocular manifestations of PACS2-associated disease, including refractive errors and strabismus, as well as less frequently reported findings such as coloboma, ptosis, and anisocoria. Patients additionally exhibited neuro-ophthalmologic manifestations of disease including nystagmus and 1.5 syndrome as well as broader neurological manifestations more typically associated with PACS2-associated disease including developmental delay and intellectual impairment, seizures, hypotonia, and features of autism spectrum disorder. Finally, patients also exhibited cardiac defects, especially septal defects, and genitourinary defects, including cryptorchidism. Patients with chromosomal deletions showed very similar phenotypes. Careful phenotyping analysis showed that pacs2-/- larvae also exhibit ocular and cardiac phenotypes.

Conclusion:
We have used a literature review and generation of zebrafish knockout mutants to provide a more comprehensive assessment of the importance of PACS2 in eye development. Patients with pathogenic variants in PACS2 and zebrafish models of reduced pacs2 function both exhibit cardiac and ocular phenotypes that support a role for this gene in early development.

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