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General Information
Name
mitochondrial complex III deficiency, nuclear type 2
FlyBase ID
FBhh0000369
Overview

This report describes mitochondrial complex III deficiency, nuclear type 2, a severe neurodegenerative disorder that is inherited as an autosomal recessive. The human gene implicated in this disease is TTC19, a nuclear-encoded subunit of mitochondrial respiratory chain complex III. There is a single fly ortholog, Dmel\Ttc19, for which RNAi-targeting constructs and alleles caused by insertional mutagenesis have been generated.

The human TTC19 gene has not been introduced into flies.

One of the phenotypes described for Dmel\Ttc19 is bang-sensitivity (FBcv:0000391), a phenotype similar to seizure sensitivity in humans; see the human disease model report for epilepsy (FBhh0000268). Several other fly genes characterized as models of mitochondrial disease also exhibit bang-sensitive phenotypes, including sesB (see mitochondrial myopathy, SLC25A4(ANT1)-related, FBhh0000372), mt:ND2 (see mitochondrial complex I deficiency, MT-ND2-related, FBhh0000382), and mt:ATPase6 (see mitochondrial complex V disorders, MT-ATP6-related, FBhh0000376).

Adult flies homozygous for a loss-of-function Dmel\Ttc19 allele show strong bang sensitivity, severely reduced spontaneous motor activity, impaired response in an optomotor test, and reduced lifespan. The complex III activity is markedly reduced in mutant flies; complex I and complex IV activities are normal. Experiments in Drosophila supported work postulating a role of human TTC19 in mitochondrial function (FBrf0213121).

[updated Aug. 2016 by FlyBase; FBrf0222196]

Disease Summary Information
Parent Disease Summary: mitochondrial complex III deficiency, nuclear type
Symptoms and phenotype

Autosomal recessive mitochondrial complex III deficiency is a severe multisystem disorder with onset at birth of lactic acidosis, hypotonia, hypoglycemia, failure to thrive, encephalopathy, and delayed psychomotor development. Visceral involvement, including hepatopathy and renal tubulopathy, may also occur. Many patients die in early childhood, but some may show longer survival (de Lonlay et al., 2001, pubmed:11528392; De Meirleir et al., 2003, oubmed:12910490 ). [from OMIM:124000; 2021.09.26]

Specific Disease Summary: mitochondrial complex III deficiency, nuclear type 2
OMIM report

[MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 2; MC3DN2](https://omim.org/entry/615157)

Human gene(s) implicated

[TETRATRICOPEPTIDE REPEAT DOMAIN-CONTAINING PROTEIN 19; TTC19](https://omim.org/entry/613814)

Symptoms and phenotype

Mitochondrial complex III deficiency nuclear type 2 (MC3DN2) is an autosomal recessive severe neurodegenerative disorder that usually presents in childhood. Affected individuals have motor disability, with ataxia, apraxia, dystonia, and dysarthria, associated with necrotic lesions throughout the brain [from OMIM:615157; 2016.08.15]

Genetics

Mitochondrial complex III deficiency nuclear type 2 (MC3DN2) is caused by homozygous or compound heterozygous mutation in the nuclear-encoded TTC19 gene. [from OMIM:615157; 2016.08.15]

Cellular phenotype and pathology
Molecular information

TTC19 (tetratricopeptide repeat domain 19) is a subunit of mitochondrial respiratory chain complex III, which transfers electrons from coenzyme Q to cytochrome c. [from OMIM:613814; 2016.08.15]

External links
Disease synonyms
complex 3 mitochondrial respiratory chain deficiency
MC3DN2
mitochondrial complex III deficiency nuclear type 2
Ortholog Information
Human gene(s) in FlyBase
    Human gene (HGNC)
    D. melanogaster ortholog (based on DIOPT)
    Comments on ortholog(s)

    One to one (1 human to 1 Drosophila).

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

          Moderate-scoring ortholog of human TTC19 (1 Drosophila to 1 human). Dmel\Ttc19 shares 25% identity and 43% similarity with the human gene.

          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 (0 groups)
            Alleles Reported to Model Human Disease (Disease Ontology) (2 alleles)
            Models Based on Experimental Evidence ( 2 )
            Modifiers Based on Experimental Evidence ( 0 )
            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.
            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
            CRISPR/Cas9
            References (8)