The HECT-domain E3 ligase EEL-1, which is homologous to human Huwe1/ARF-BP1/Mule, was shown to genetically behave like SIR-2.1 (Ross et al. 2011), as does KRI-1, the ortholog of human KRIT1/CCM1, a gene frequently mutated in the neurovascular disease cerebral cavernous malformation (Ito et al. 2010) (see below). Here, HUWE1 is linked to famililal cerebral cavernous malformations.