Effect on UBA 1 Function
UBA 1 is the primary factor behind the production of ubiquitin-activating enzyme E1, which is essential for the activation of the ubiquitin-proteasome system. The gene encodes for a protein, which catalyses the first step in ubiquitination. This is a defence mechanism, marking unnecessary cellular proteins and stimulating their breakdown.
Usually, UBA has two notable isoforms –
UBA 1a – translation is initiated at p.Met1
UBA 1b – translation is initiated at p.Met41
The mutations, causing the variants, described previously, lead to the formation of an unorthodox UBA 1c isoform, which arises from mutations at Met67.
UBA 1c isoform is hindered in its catalytic function.
The mutations resulting in the variants found in VEXAS favour the formation of the catalytically impaired UBA 1c isoform, over the catalytically proficient UBA 1b isoform. (4)