The Original Study
NIH’s Undiagnosed Diseases Program was established in 2008, with the aim
of investigating and providing a scientific rationale for diseases
presented by patients for which a firm diagnosis was not possible to
make. (3) Genetic data of 2560 individuals from this program were
analysed, from which the first three male participants, identified as
having missense mutations in codon 41 in UBA 1 were recognized. (4) 15
other men were also identified on the basis of correspondence in
observational cohorts at the NIH Clinical Centre, and 7 other men were
also identified in similar study populations at the UCL and Leeds
Teaching Hospital NHS Trusts in the UK. (1) Peripheral Blood Exome
sequences in these 25 patients were isolated. These men were reported to
have one of three somatic variants in methionine-41 (p.Met41Val,
p.Met41Thr, p.Met41Leu) in UBA 1, which is a major E1 enzyme responsible
for initiating the process of ubiquitylation. These mutations triggered
a loss of the canonical cytoplasmic isoform of UBA 1 and caused mutant
peripheral blood cells, which collectively activated self-attacking
immune
pathways, reduced ubiquitylation, and promoted systemic inflammation.
This learning was then used to unite clinical demonstrations, which have
been discussed in the following sections. (1)