Höfundar:
Kaan Okay, Katrín Möller, Kasper Daniel Hansen, Hans Tómas Björnsson
Introduction:
Given nonsense mediated decay, loss of function variants (LOFs) are often functionally equivalent irrespective of location. In contrast, Pathogenic Missense Variants (PMVs) primarily occur in functional domains and thus can be used to identify critical domains. We have calculated PMV enrichment in a subset of the EM to identify the most critical protein domains in this group, and this has led to a plausible mechanistic hypothesis to explain how CREBBP and EP300 can lead to two distinct phenotypes.
Methods:
The PMVs were obtained from ClinVar and benign variants from gnomAD. Fisher’s exact test was performed to determine the enrichment of PMVs in domains within EM genes.
Results:
Variants in CREBBP and EP300 lead to four phenotypes: Rubinstein-Taybi syndromes 1&2 (RTS) and Menke-Hennekam syndromes 1&2 (MHS). The PMV enrichment in MHS is driven by enrichment in ZZ (OR = 16.3, adj-p = 0.005), TAZ-type (OR = Inf, adj-p = 0.0003), and an uncharacterized domain (OR = Inf, adj-p = 0.002). In contrast, the PMV enrichment in RTS is driven by HAT domains in both genes. The ZZ domain binds to the SUMO-1 protein to mediate intramolecular SUMOylation of CREBBP and EP300.
Conclusion:
Our results suggest that the MHS associated with CREBBP and EP300 may be caused by disruption in intramolecular SUMOylation of CREBBP and EP300, while the RTS seen in both genes may be caused by an abnormality of histone acetylation.