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)