• Mitchell syndrome

This report describes Mitchell syndrome (MITCH), a newly described neurogenerative disease that affects young children. The gene implicated in this disease is ACOX1, which encodes peroxisomal acyl-CoA oxidase. In the 3 cases of this disease described thus far, the same missense mutation (N237S) occurred de novo and caused disease pathology when heterozygous. The highest-scoring ortholog in Drosophila is also designated ACOX1; loss-of-function mutations, a gain-of-function allele analogous to human N237S, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\ACOX1.

Multiple UAS constructs of the human Hsap\ACOX1 have been introduced into flies, including wild-type and the variant form implicated in this disease. Experiments in flies support findings that the N237S variant stabilizes ACOX1 as an active dimer, acts as a gain-of-function mutation, and produces elevated levels of reactive oxygen species (ROS) in insulating glia.

Variant(s) implicated in human disease tested (as transgenic human gene, ACOX1): the N237S variant form of the human gene has been introduced into flies. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): N250S in the fly ACOX1 gene (corresponds to N237S in the human ACOX1 gene).

Animals homozygous for loss-of-function alleles of Dmel\ACOX1 typically die during the pupal stage; adult escapers exhibit progressive neurodegenerative phenotypes. Ubiquitous overexpression of wild-type Dmel\ACOX1 causes a 25% reduction in the number of animals that eclose; surviving adults do not exhibit any obvious behavioral defects. In contrast, ubiquitous expression of a fly gene carrying the missense mutation analogous to that implicated in Mitchell syndrome results in much more extreme 80% reduction in the number of animals that eclose. The animals that survive to adulthood are unable to fly, walk, or feed, and they die in less than 2 days. A small number of physical and genetic interactions of Dmel\ACOX1 have been described; see below and in the ACOX1 gene report.

This model system has supported development of a candidate pharmaceutical intervention.

A neurodegenerative disease caused by loss-of-function variants in human ACOX1 has also been studied in flies; see ‘peroxisomal acyl-CoA oxidase deficiency’ (FBhh0001230). Both loss and gain of ACOX1 lead to glial and neuronal loss, but by different mechanisms, thus requiring different treatments.

[updated Jul. 2020 by FlyBase; FBrf0222196]