UNC45A-related osteo-oto-hepato-enteric syndrome in a Chinese neonate.

Unexplained diarrhea and cholestasis are common clinical phenotypes in newborns, indicating there is only a little common genetic basis for these conditions. However, it has been reported that defects in the UNC45A gene can lead to osteo-oto-hepato-enteric syndrome. However, to date, only 10 patients with this syndrome have been reported in 2 studies; therefore, there is still a lack of analysis regarding the correlation between disease phenotype and genotype. Trio-whole exome sequencing was conducted using DNA samples from a newborn with congenital diarrhea and cholestasis from a Chinese Han family. The UNC45A variants were verified using Sanger sequencing. In addition, we applied a crystal structure model to analyze the potential hazards associated with the variants. The plasmids were constructed in vitro and transfected into human 293T cells for Western blot (WB) analysis. After the mutant protein was fused with the Green Fluorescent Protein label, intracellular localization was observed using laser confocal microscopy. The gene detection results showed that the UNC45A gene of the newborn examined in the present study harbored the compound heterozygous variants p.Arg819Ter, and p.Leu237Pro; this was confirmed via Sanger sequencing. Analysis of the Leu237Pro crystal structure model suggested that this variant may decrease local structural stability and affect protein function. The Western blot and laser confocal microscopy observation results suggested that the Leu237Pro mutation leads to reduced protein expression, while the Arg819Ter mutation completely inhibits the expression of the protein. The compound heterozygous variants of UNC45A (p.Arg819Ter and p.Leu237Pro) may be pathogenic factors of congenital diarrhea and cholestasis in this neonatal patient. Therefore, UNC45A deficiency should be considered when intractable diarrhea and cholestasis occur in newborns.