UNC45A belongs to the UCS protein family (UNC-45/CRO1/She4p). C. elegans unc-45 was first described after a screening for mutations causing motility disorders (UNC stands for uncoordinated). The UNC-45 protein has three recognizable domains: an N-terminal tetratricopeptide repeat (TRP) domain (∼115 amino acids), a central domain of ∼400 amino acids, and a C-terminal UCS domain (∼400 amino acids). The TPR domain participates in protein-protein interactions, especially with Hsp70 (HSPA1A) and Hsp90 HSP90AA1. The role of the central domain remains unclear, while the C-terminal UCS domain is critical for myosin binding. Whether or not variants located within specific domains of UNC45A lead to different functional outcomes is still unknown. UNC45A appears to be ubiquitously expressed and has been postulated to be involved in cytoskeletal functions, such as cell division or exocytosis.
The UNC45A gene has been discovered by trio whole-exome-sequencing in three families. O2HE syndrome is an autosomal recessive disorder. Most of the mutations are inherited from healthy parents. Patients present with compound heterozygous status, or homozygous in related parents. In vitro and in vivo functional studies of the UNC45A gene indicated a loss-of-function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut development and function.