ARMC9 is lesser known protein, containing N-terminal LisH (Lissencephaly type 1 like homology) domain and C-terminal ARM (Armadillo repeats) motifs. ARM repeats are characterized as repeating 42 amino acid motifs, composed of three alfa helices. ARM repeat containing proteins do not share sequence similarity but structurally they are similar. Multiple ARM repeats fold together to form a super helix structure, that acts as platform for interaction with other protein partners. ARMC9 localizes at the basal body and at the daughter centriole of the primary cilium. Disruption of ARMC9 modulates ciliary length, axonemal post translational modification (acetylation and polyglutamylation) and ciliary stability. CRISPR/Cas9 engineered frameshift mutations in Zebrafish also shows similar phenotype to Joubert syndrome including curved body shape (ciliopathy phenotype), reduction in cilia numbers and coloboma.
Till now 15 pathogenic variants have been reported in ARMC9. A total of 7 missense, 3 non-sense, 2 splice site, 1 frameshift deletion, 1 in-frame insertion caused by splice site variant and 1 in-frame deletion caused by synonymous splice site variant have been reported. Additionally, Clinvar has reports on 9 frameshift, 3 non-sense, and 1 splice-site pathogenic / likely pathogenic variants.
Functional studies and Zebrafish modelling indicates loss of function mechanism for pathogenic variants in ARMC9 for causing Joubert Syndrome 30.
ARMC9