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)