IKBKG (NEMO) 5′ Untranslated Splice Mutations Lead to Severe, Chronic Disseminated Mycobacterial Infections

Abstract

Four patients with adult-onset, disseminated mycobacterial infection had 5' UTR mutations in IKBKG without clear physical stigmata of NEMO deficiency. These mutations caused decreased levels of NEMO protein and Toll-like receptor driven cytokine production. Three patients died from disseminated disease. These mutations may be missed by whole exome sequencing.

Mendelian susceptibility to mycobacterial disease: 2014–2018 update

“…Since the discovery of its first genetic etiology in 1996, MSMD has been reported and a causal genetic lesion described in 501 individuals from 356 kindreds originating from 57 countries on five continents (Figure a). Over this period, the genetic dissection of MSMD in these patients has revealed this condition to be caused by inborn errors of interferon (IFN)‐γ immunity . These findings confirm that IFN‐γ, first described in 1965 as an antiviral IFN, is actually the macrophage‐activating factor, as shown in 1983 .…”

“…One of these mutations (c.1‐16G>C) is located in the noncoding exon 1B of NEMO . Three patients harboring this mutation presented adulthood‐onset disseminated mycobacterial disease . Another patient with the same phenotype carried the previously described c.1‐16+1G>T NEMO mutation .…”

“…Since the last comprehensive review on MSMD in 2014, three new genetic disorders have been reported, caused by mutations of TYK2 and SPPL2A, (two novel genetic etiologies) and IFNGR2 (a novel allelic form). Moreover, new mutations associated with the other 18 disorders have also been reported . We also discuss here two recently reported syndromic forms of MSMD: AR RORγ/RORγT and Janus kinase (JAK)1 deficiencies .…”

“…Since 2014, 34 new disease‐causing mutations have been reported at six MSMD loci already discovered before this date, including IFNGR1, IFNGR2 , IL12RB1 , IL12B , STAT1 and NEMO . Interestingly, the two new hypomorphic NEMO mutations underlie mycobacterial diseases without anhidrotic ectodermal dysplasia . One of these mutations (c.1‐16G>C) is located in the noncoding exon 1B of NEMO .…”

“…Interestingly, the two new hypomorphic NEMO mutations underlie mycobacterial diseases without anhidrotic ectodermal dysplasia . One of these mutations (c.1‐16G>C) is located in the noncoding exon 1B of NEMO . Three patients harboring this mutation presented adulthood‐onset disseminated mycobacterial disease .…”