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General Information
Name
Mitchell syndrome
FlyBase ID
FBhh0001229
Disease Ontology Term
Parent Disease
Overview

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]

Disease Summary Information
Disease Summary: Mitchell syndrome
OMIM report

[MITCHELL SYNDROME; MITCH](https://omim.org/entry/618960)

Human gene(s) implicated

[ACYL-CoA OXIDASE 1, PALMITOYL; ACOX1](https://omim.org/entry/609751)

Symptoms and phenotype

Mitchell syndrome (MITCH) is a progressive disorder characterized by episodic demyelination, sensorimotor polyneuropathy, and hearing loss (Chung et al., 2020; pubmed:32169171). [from OMIM:618960; 2020.07.27]

Genetics

The heterozygous mutations in the ACOX1 gene that were identified in patients with Mitchell syndrome by loss Chung et al. (pubmed:32169171) occurred de novo. [from OMIM:618960; 2020.07.27]

Cellular phenotype and pathology
Molecular information

The protein encoded by ACOX1, peroxisomal acyl-CoA oxidase, is the first enzyme of the fatty acid beta-oxidation pathway, which catalyzes the desaturation of acyl-CoAs to 2-trans-enoyl-CoAs. It donates electrons directly to molecular oxygen, thereby producing hydrogen peroxide. [Gene Cards, ACOX1; 2020.07.27]

Peroxisomal beta-oxidation of fatty acids is catalyzed by enzymes that are immunologically distinct from the analogous mitochondrial enzymes. The ACOX1 gene encodes peroxisomal acyl-CoA oxidase, the first and rate-limiting enzyme in the peroxisomal fatty acid beta-oxidation pathway. [from OMIM:609751; 2020.07.27]

External links
Disease synonyms
MITCH
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to many: multiple related genes in both species.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Cellular component (GO)
    Gene Groups / Pathways
    Comments on ortholog(s)

    Highest-scoring ortholog of human ACOX1; additional related genes in both species. Dmel\ ACOX1 shares 44% identity and 63% similarity with human ACOX1.

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Other Genes Used: Viral, Bacterial, Synthetic (0)
      Summary of Physical Interactions (2 groups)
      protein-protein
      Interacting group
      Assay
      References
      Alleles Reported to Model Human Disease (Disease Ontology) (5 alleles)
      Models Based on Experimental Evidence ( 2 )
      Modifiers Based on Experimental Evidence ( 3 )
      Models Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Interaction
      References
      Alleles Representing Disease-Implicated Variants
      Genetic Tools, Stocks and Reagents
      Sources of Stocks
      Contact lab of origin for a reagent not available from a public stock center.
      Bloomington Stock Center Disease Page
      Selected mammalian transgenes
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila transgenes
      Allele
      Transgene
      Publicly Available Stocks
      RNAi constructs available
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila classical alleles
      Allele
      Allele class
      Mutagen
      Publicly Available Stocks
      amorphic allele - molecular evidence
      gene targeting by homologous recombination
      References (7)