Exploring the Genetic Landscape of Childhood Glaucoma

Abstract

Childhood glaucoma, a significant cause of global blindness, represents a heterogeneous group of disorders categorized into primary or secondary forms. Primary childhood glaucoma stands as the most prevalent subtype, comprising primary congenital glaucoma (PCG) and juvenile open-angle glaucoma (JOAG). Presently, multiple genes are implicated in inherited forms of primary childhood glaucoma. This comprehensive review delves into genetic investigations into primary childhood glaucoma, with a focus on identifying causative genes, understanding their inheritance patterns, exploring essential biological pathways in disease pathogenesis, and utilizing animal models to study these mechanisms. Specifically, attention is directed towards genes such as CYP1B1 (cytochrome P450 family 1 subfamily B member 1), LTBP2 (latent transforming growth factor beta binding protein 2), TEK (TEK receptor tyrosine kinase), ANGPT1 (angiopoietin 1), and FOXC1 (forkhead box C1), all associated with PCG; and MYOC (myocilin), associated with JOAG. Through exploring these genetic factors, this review aims to deepen our understanding of the intricate pathogenesis of primary childhood glaucoma, thereby facilitating the development of enhanced diagnostic and therapeutic strategies.

Keywords: ANGPTI; CYP1B1; FOXC1; LTBP2; MYOC; TIE2; childhood glaucoma; genetic.

Figure 1

Gene structure of CYP1B1 and the locations of the most prevalent mutations associated with primary congenital glaucoma (PCG). The most common mutations reported across different populations are indicated in red, while mutations specific to certain populations are shown in black.

Figure 2

Gene structure of LTBP2 and variants associated with primary congenital glaucoma (PCG). The LTBP2 gene comprises 36 exons and codes a protein of 1821 amino acids, characterized by EGF-like (E), TB (T), and calcium-binding EGF-like (C) domains.

Figure 3

Gene structure of TEK and identified primary congenital glaucoma (PCG) variants. The TEK gene consists of 23 exons and codes a protein of 1124 amino acids, featuring Ig-like (Ig), EGF-like (EGF), fibronectin type III (FN III), and protein kinase (Kinase) domains. Variants reported in PCG patients are depicted, excluding those located in intronic regions: c.1624+5G>A, c.760+2T>C, and c.3300+2delT. Asterisk (*): premature stop codon.

Figure 4

Schematic representation of the ANGPT1 gene structure, protein domains, and three reported primary congenital glaucoma (PCG) mutations. The ANGPT1 gene comprises nine exons and codes for a protein of 498 amino acids, characterized by two coiled-coil (CC) domains and one fibrinogen C-terminal domain. Asterisk (*): premature stop codon.

Figure 5

Gene structure of MYOC and reported 12 primary congenital glaucoma (PCG) variants by multiple independent research groups. The MYOC gene consists of 3 exons and encodes a protein of 504 amino acids, including one coiled-coil (CC) and one olfactomedin-like (OLF) domain. Asterisk (*): premature stop codon.