ClinVar

In 7 unrelated patients with childhood-onset neurodegeneration with brain atrophy (CONDBA; 617672), Edvardson et al. (2017) identified a recurrent de novo heterozygous c.628G-A transition (c.628G-A, NM_014233.3) in the UBTF gene, resulting in a glu210-to-lys (E210K) substitution at a conserved residue in the second HMG-box homology domain. This residue is followed by 2 lysine residues; thus the mutation would result in a string of 3 lysine residues, conferring a highly positively charged region. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Studies of fibroblasts derived from 1 patient showed that the mutation resulted in a gain of function and increased expression of ribosomal subunit 18S.

Toro et al. (2018) identified a recurrent de novo heterozygous E210K mutation in the UBTF gene in 4 unrelated patients with CONDBA. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Studies of patient fibroblasts showed that the mutant protein was expressed normally and showed normal nucleolar localization. However, patient cells had increased expression of pre-rRNA and 18S rRNA compared to controls, suggesting a gain of function. There were also abnormalities in the expression of putative UBTF2 targets. Patient fibroblasts showed increased DNA double-strand breaks, failure of progression to the G2 phase of the cell cycle, and a tendency towards apoptotic cell death. There was a trend for UBTF E210K fibroblasts to harbor fewer nucleoli per nucleus compared to controls, but there was no significant effect of the mutation on nucleolar area.