Genetic variants in PIKFYVE: A review of ocular phenotypes

• Published in: Experimental eye research 2024-12, Vol.251, p.110211
• Main Authors: Misaghi, Ehsan, Kannu, Peter, MacDonald, Ian M, Benson, Matthew D
• Format: Article
• Language: English
• ISSN: 1096-0007; 1096-0007
• DOI: 10.1016/j.exer.2024.110211

Many studies have identified disease-causing variants of PIKFYVE in ocular tissues; however, a comprehensive review of these variants and their ocular phenotypes is lacking. The phosphoinositide kinase PIKFYVE plays crucial roles in the endolysosomal pathway in autophagy and phagocytosis, both essential for cellular homeostasis. In this review, we evaluate the reported disease-causing PIKFYVE variants and their associated phenotypes in humans to identify potential genotype-phenotype correlations. Variants in PIKFYVE have been associated with corneal fleck dystrophy, congenital cataracts and possibly keratoconus. There are unvalidated associations of variants in PIKFYVE with autism spectrum disorder and congenital heart disease. We show that variants causing corneal fleck dystrophy exist in the chaperonin-like domain of PIKFYVE as well as the region between the chaperonin-like and the kinase domains. Similarly, congenital cataract variants appear to be specific to the kinase domain of the protein. This review consolidates existing knowledge on PIKFYVE variants in ocular disease and bridges fundamental science and clinical manifestations, potentially informing future diagnostic and treatment strategies for PIKFYVE-associated ocular disorders.