KBTBD4
Overview
KBTBD4 (Kelch Repeat And BTB Domain Containing 4) encodes a BTB-Kelch domain protein that functions as a substrate adaptor for CUL3-RING ubiquitin ligase complexes. In medulloblastoma, KBTBD4 harbors recurrent in-frame insertions in its Kelch domain that are highly enriched in specific methylation subtypes, suggesting a neomorphic substrate-recognition mechanism rather than simple loss of function.
Alterations observed in the corpus
- Recurrent in-frame insertions in the Kelch domain (residues 308–313); 18/20 KBTBD4 variants were in-frame indels in medulloblastoma PMID:28726821
- Predominant Group 3 insertion: R313delinsPRR; predominant Group 4 insertion: P311delinsPP PMID:28726821
- Highly enriched in methylation subtypes II (21%) and VII (14%); homology modelling places insertions on the substrate-binding interface, suggesting altered substrate recognition rather than loss of fold PMID:28726821
Cancer types (linked)
- Medulloblastoma (Group 3 and Group 4): Recurrent in-frame Kelch domain insertions enriched in methylation subtypes II and VII, making KBTBD4 one of the most distinctive alteration patterns in these subgroups PMID:28726821
Co-occurrence and mutual exclusivity
- Enriched in medulloblastoma methylation subtypes II and VII; subtype distribution overlaps with Group 3 and Group 4 biology PMID:28726821
Therapeutic relevance
- The neomorphic substrate-recognition model (altered Kelch-domain substrate binding) could present a vulnerability, but no direct therapeutic targeting has been reported.
Open questions
- The identity of the ubiquitination substrate(s) affected by KBTBD4 Kelch insertions and how altered substrate recognition drives medulloblastoma pathogenesis remain to be defined.
Sources
This page was processed by entity-page-writer on 2026-05-15.