Mutations in the Drosophila ari-1 gene, which encodes an E3 ubiquitin ligase, result in nuclear clustering and morphology defects in larval muscles. One of the substrates of the encoded protein is the LINC complex member koi (see the human disease model report 'Emery-Dreifuss muscular dystrophy, LINC-complex-related', FBhh0000812). These and other observations led to investigation of whether the human ortholog, ARIH1, is associated with disease. Exome sequencing identified three unrelated individuals with early-onset or familial thoracic aortic aneurysm or dissection with rare variants in ARIH1. Although multiple similar genes exist in both species, Dmel\ari-1 and human ARIH1 are most closely related to each other. Classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\ari-1.
Multiple UAS constructs of the human Hsap\ARIH1 have been introduced into flies, including wild-type and variants implicated in disease. Significant heterologous rescue (functional complementation) is observed for the Dmel\ari-1 nuclear clustering phenotype found in third instar larval muscles and the lethality/reduced lifespan of adults; the disease-associated variants fail to rescue or weakly rescue. Variant(s) implicated in human disease tested (as transgenic human gene, ARIH1): the E15Q, E44G, and R171* variant forms have been introduced into flies.
Animals homozygous for loss-of-function mutations of Dmel\ari-1 typically die during the pupal stage; escapers exhibit locomotor defects and reduced lifespan. Nuclear clustering is observed in third instar larval body wall muscles. In mosaic analyses, homozygous clones exhibit neurophysiology defects. Physical and genetic interactions of Dmel\ari-1 have been described, see below and in the ari-1 gene report. Genetic interactions with Dmel\park, the fly ortholog of the gene implicated in Parkinson disease 2 (see that human disease model report, FBhh0000008), suggest that the ari-1 and park proteins are partially functionally redundant.
Relevant to the observed physical and genetic interactions with koi and park, it has been noted that the rate of cardiac disease is elevated in patients suffering from Parkinson disease or muscular dystrophy.
[updated Jul. 2018 by FlyBase; FBrf0222196]
ARIH1 encodes an E3 ubiquitin-protein ligase, which catalyzes ubiquitination of target proteins together with ubiquitin-conjugating enzyme E2 UBE2L3. [Gene Cards, ARIH1; 2018.07.03]
Many to many: 3 human to 3 Drosophila; the human genes are ARIH1, ARIH2, and ANKIB1. Expression of Dmel\CG12362 is restricted to testis.
High-scoring ortholog of human ARIH1 (reciprocal best hit); low- to moderate-scoring ortholog of human ARIH2 and ANKIB1 (3 Drosophila to 3 human). Dmel\ari-1 shares 61% identity and 73% similarity with human ARIH1.
