Gene and Protein Function
WDR83OSencodes a small 106-amino acid protein known as Asterix, located on the opposite strand of the WDR83gene. Asterix heterodimerizes with CCDC47 to form the PAT complex, a chaperone system associated with the endoplasmic reticulum (ER) translocon. The PAT complex facilitates proper folding of large transmembrane proteins by shielding hydrophobic residues during insertion into the ER membrane.
Mutation Spectrum
All reported pathogenic variants are biallelic loss-of-function (LoF) mutations. Types of mutations:
• Nonsense mutations (e.g., c.235C>T, p.Gln79*; c.70G>T, p.Glu24*): introduce premature stop codons.
• Canonical splice site mutations (e.g., c.156+1G>T, c.156+2T>A, c.50+1G>T): disrupt normal splicing, leading to exon skipping and frameshifts.
• Small deletions (e.g., c.255-4_260del): affect splice acceptor sites and coding sequence.
Predicted Molecular Consequences
• SpliceAI predicts high probability of splice donor loss for all canonical splice site variants.
• RT-PCR confirmed exon skipping for c.156+1G>T, resulting in a truncated protein (p.Arg17Serfs*2).
• All mutations are predicted to disrupt one or both transmembrane domains, likely impairing subcellular localization and function of Asterix.
Pathophysiologic Mechanism
Loss of Asterix disrupts the PAT complex, impairing ER-associated folding of transmembrane proteins. This may lead to:
• ER stress and downstream cellular dysfunction.
• Defective bile acid transport or tight junction integrity, resulting in hypercholanemia and pruritus.
• Impaired lipid absorption, contributing to poor growth and fat-soluble vitamin deficiency.
• Neurodevelopmental impairment, possibly due to disrupted folding of neuronal membrane proteins.
WDR83OS