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General Information
Alzheimer disease, susceptibility to, TOMM40-related
FlyBase ID
Disease Ontology Term
Parent Disease

Multiple GWAS studies have implicated the human gene TOMM40 in the development of late-onset Alzheimer disease. TOMM40, which encodes the channel subunit of the mitochondrial outer membrane (TOM) complex, is a core component of the mitochondrial protein-importing system. The most closely related gene in Drosophila is Tom40, for which RNAi targeting constructs and an allele caused by insertional mutagenesis have been generated. Two paralogous genes in Drosophila, tomboy40 and CG4520, are expressed predominantly in testis.

The human TOMM40 gene has not been introduced into flies.

Animals homozygous for a severe loss-of-function mutation of Dmel\Tom40 die in the embryonic stage. Assessed in the larval fat body cells, reduced levels of Tom40 effected by RNAi result in accumulation of ubiquitin-positive protein aggregates engulfed by autophagosome-like membranes. The protein aggregates contain mitochondrial preproteins, cytosolic proteins, and proteasome subunits. Autophagy is induced, but the majority of autophagosomes fail to fuse with lysosomes. Reduced levels of Tom40 in the nervous system also results in protein aggregate formation and subsequent degeneration of neurons. A small number of physical and genetic interactions for Dmel\Tom40 have been described; see below and in the Tom40 gene report.

[updated Feb. 2020 by FlyBase; FBrf0222196]

Disease Summary Information
Parent Disease Summary: Alzheimer disease
Symptoms and phenotype

Alzheimer disease (AD) is the most common form of progressive dementia in the elderly. [from OMIM:104300; 2016.01.08]

Memory loss is the most common sign of Alzheimer disease. As the disorder progresses, some people with AD experience personality and behavioral changes; other common symptoms include agitation, restlessness, withdrawal, and loss of language skills. Total care is usually required during the advanced stages of the disease. Affected individuals usually survive 8 to 10 years after the appearance of symptoms, but the course of the disease can range from 1 to 25 years. Death usually results from pneumonia, malnutrition, or general body wasting. [from Genetics Home Reference, Alzheimer disease; 2016.01.08]

Alzheimer disease can be classified as early-onset or late-onset. The signs and symptoms of the early-onset form appear before age 65, while the late-onset form appears after age 65. The early-onset form is much less common than the late-onset form, accounting for less than 5 percent of all cases of Alzheimer disease. [from Genetics Home Reference, Alzheimer disease; 2016.01.08]

Specific Disease Summary: Alzheimer disease, susceptibility to, TOMM40-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype

Multiple GWAS studies have implicated TOMM40 in the development of late-onset Alzheimer disease (see GWAS Catalog, below in 'External links').

Cellular phenotype and pathology
Molecular information

TOMM40 encodes a protein that is localized in the outer membrane of the mitochondria. It is the channel-forming subunit of the translocase of the mitochondrial outer membrane (TOM) complex that is essential for import of protein precursors into mitochondria. [Gene Cards, TOMM40; 2020.02.11]

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

    Many to many: 2 human to 3 Drosophila.

    Other mammalian ortholog(s) used
      D. melanogaster Gene Information (1)
      Gene Snapshot
      Translocase of outer membrane 40 (Tom40) encodes a protein predicted to be a channel component of the TOM complex, which is involved in protein import into mitochondria. It is predicted to be involved in the cellular response to hypoxia. [Date last reviewed: 2019-03-14]
      Gene Groups / Pathways
        Comments on ortholog(s)

        High-scoring ortholog of human TOMM40; moderate-scoring ortholog of human TOMM40L. Dmel\Tom40 shares 41-52% identity and 59-65% similarity with the human genes. Additional related genes in flies are tomboy40 and CG4520; expression of both of these genes is testis-enriched, with little or no neural expression.

        Orthologs and Alignments from DRSC
        DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
        Synthetic Gene(s) Used (0)
        Summary of Physical Interactions (2 groups)
        Interacting group
        anti bait coimmunoprecipitation, peptide massfingerprinting
        pull down, autoradiography
        Alleles Reported to Model Human Disease (Disease Ontology) (0 alleles)
        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
        Publicly Available Stocks
        Selected Drosophila transgenes
        Publicly Available Stocks
        RNAi constructs available
        Publicly Available Stocks
        Selected Drosophila classical alleles
        Allele class
        Publicly Available Stocks
        References (3)