Table 2 Architectural proteins and their disease associations in humans.
From: Enhancer–promoter specificity in gene transcription: molecular mechanisms and disease associations
Protein/Protein complex | Disease association | Mutation | Molecular mechanism | Refs. |
|---|---|---|---|---|
CTCF | breast, kidney, prostate cancer; leukemias; endometriosis; endometriosis-associated neoplasia | CTCF copy number aberrations, N-terminal mutations p.Gly19*, pThr204fs*26, K206E, and DBD (ZnF1-5) mutations R278C, H284N/P/Y, L309P, R339Q/W, R342H, K344E, H345R K365T, H373L, R377C/H, P378L, R448Q; also see Fig. 3 | changes in CTCF protein levels; altered CpG methylation patterns; modified CTCF DNA-binding profile | |
neurodevelopmental disorders; cardiac defects | numerous DBD and non-DBD frameshifts, including p.Gly111fs*29, pVal126Cysfs*14, p.Lys206Profs*13/15, pArg396Lysfs*13; missense mutations in DBD ZnF (e.g., D390N, R567W); also see Fig. 3 | altered CTCF binding or not determined | ||
multiple cancer types; neurodegenerative disease; severe influenza; hearing loss; osteoporosis | CTCF binding site mutations | loss of CTCF binding | ||
Cohesin | Cornelia de Lange syndrome | NIPBL, SMC1A, SMC3, RAD21 Indel, frameshift, missense mutations | multiple, including defective DNA repair, chromosome instability, and disruption of TADs/E-P interactions | |
peripheral sclerocornea | RAD21 A622T | dysregulated cohesin binding | ||
chronic intestinal pseudo-obstruction/Mungan syndrome | RAD21 R450C | separase cleavage site in RAD21 | ||
Condensin | neurodevelopmental disorders | NCAPH, NCAPD2 missense and splice site mutations; NCAPD3 frameshift, intronic mutation creating a de novo splice site | impaired chromosome segregation and chromosome structural integrity | |
neurological disorders, nervous system tumors | NCAPH2, NCAPG2, NCAPD2, NCAPH deletion and haploinsufficiency; SMC2, SMC4, NCAPG2 overexpression | multiple, including defective DNA repair and TGFβ pathway activation | ||
MeCP2 | Rett syndrome | deletions and missense mutations, predominantly in methyl-binding and corepressor interacting domains | transcriptional derepression; loss of repressive chromatin looping | |
YY1 | neurological diseases, intellectual disability syndrome | deletions and missense mutations resulting in haploinsufficiency | loss of YY1 binding at low occupancy sites; reduced H3K27ac on cognate YY1 enhancers |
