Edgar identified a new secretion protein using secretion cloning to screen the secretion protein of Xenopus gastrula embryos. It was named Xenopus isthmin (xISM), because it is mainly expressed at the middle hindbrain boundary (MHB) [1]. The full-length xIsm cDNA clone encodes a 449 amino acid protein, including a hydrophobic signal peptide at the N-terminus responsible for directing secreted proteins to the endoplasmic reticulum and Golgi apparatus [2], a thrombospondin type 1 repeat domain at the center, and an adhesion-related domain of MUC4 and other protein (AMOP) domains at the C-terminus [1], [2]. Trp223 and Trp226 in human ISM-1 are C-mannosylated and regulate the intracellular transport of ISM-1 from the endoplasmic reticulum to the Golgi apparatus. N-mannosylation of human ISM-1 at Asn39 and Asn285 is induced when C-mannosylation is lacking [2] [Fig. 1].

Human isthmin (hIsm) shares 78 % amino acid identity with xIsm [1]. The genomic locus of hIsm comprises six exons spanning 77.7 kb on chromosome 20p12.1 [1]. Mouse ISM-1 encodes a 461 amino acid protein on chromosome 2 with a predicted size of 52 KDa [3]. Clustal Omega analysis revealed high homology between ISM-1 orthologs when compared to the ISM-1 protein sequence between humans, mice, chicks, zebrafish, frogs, anoles, and turtles. Mouse ISM-1 shares 93 % similarity with humans [3].

In this review, we briefly introduce the structure of isthmin and expand upon the physiological underpinnings driving its pathogenesis and progression, thereby contributing to a better understanding of the function of isthmin and providing prevention and treatment strategies for various diseases.