| Popis: |
A20 haploinsufficiency (HA20) is an autoinflammatory disease caused by heterozygous loss-of-function variations in TNFAIP3, the gene encoding the A20 protein. Diagnosis of HA20 is challenging due to its heterogeneous clinical presentation and the lack of pathognomonic symptoms. While the pathogenic effect of TNFAIP3 truncating variations is clearly established, that of missense variations is difficult to determine. Herein, we identified a novel TNFAIP3 variation, p.(Leu236Pro), located in the A20 Ovarian Tumor (OTU) domain and demonstrated its pathogenicity. In the patients’ primary cells, we observed reduced A20 levels explained by enhanced degradation. We showed a disrupted ability of A20_Leu236Pro to inhibit the NF-κB pathway. Review of previously reported TNFAIP3 missense variations revealed that only 3/7 are pathogenic. Through structural modeling we showed that the residues involved in OTU pathogenic missense variations establish common interactions. Interpretation of newly identified missense variations is challenging, requiring, as illustrated here, functional demonstration of their pathogenicity. Together with functional studies, in-silico structure analysis is a valuable approach that allowed us to unveil a region within the OTU domain critical for A20 function. |
