Article

Mutation of zebrafish dihydrolipoamide branched-chain transacylase E2 results in motor dysfunction and models maple syrup urine disease

Molecular and Cellular Biology Graduate Program, Biology Department, University of Massachusetts, Amherst, MA 01003, USA.
Disease Models and Mechanisms (Impact Factor: 4.97). 11/2011; 5(2):248-58. DOI: 10.1242/dmm.008383
Source: PubMed

ABSTRACT

Analysis of zebrafish mutants that demonstrate abnormal locomotive behavior can elucidate the molecular requirements for neural network function and provide new models of human disease. Here, we show that zebrafish quetschkommode (que) mutant larvae exhibit a progressive locomotor defect that culminates in unusual nose-to-tail compressions and an inability to swim. Correspondingly, extracellular peripheral nerve recordings show that que mutants demonstrate abnormal locomotor output to the axial muscles used for swimming. Using positional cloning and candidate gene analysis, we reveal that a point mutation disrupts the gene encoding dihydrolipoamide branched-chain transacylase E2 (Dbt), a component of a mitochondrial enzyme complex, to generate the que phenotype. In humans, mutation of the DBT gene causes maple syrup urine disease (MSUD), a disorder of branched-chain amino acid metabolism that can result in mental retardation, severe dystonia, profound neurological damage and death. que mutants harbor abnormal amino acid levels, similar to MSUD patients and consistent with an error in branched-chain amino acid metabolism. que mutants also contain markedly reduced levels of the neurotransmitter glutamate within the brain and spinal cord, which probably contributes to their abnormal spinal cord locomotor output and aberrant motility behavior, a trait that probably represents severe dystonia in larval zebrafish. Taken together, these data illustrate how defects in branched-chain amino acid metabolism can disrupt nervous system development and/or function, and establish zebrafish que mutants as a model to better understand MSUD.

Download full-text

Full-text

Available from: Gerald Downes, Sep 03, 2014
  • Source
    • "In this review, I have chosen to focus on XLMR (also called Fragile X syndrome, FXS) a common inherited form of mental retardation which affects around 1 in 4000 people. However, zebrafish have also been used to examine other types of mental retardation (for recent studies, refer to Komoike et al., 2010; Song et al., 2010; Brockschmidt et al., 2011; Friedrich et al., 2012; Veleri et al., 2012; Aspatwar et al., 2013). The symptoms of FXS include mental retardation, epilepsy, autistic-like behavior, attention deficits, macroorchidism, and mild craniofacial defects which have been linked to the maturation of dendritic spines during development. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Psychiatric disorders are a diverse set of diseases that affect all aspects of mental function including social interaction, thinking, feeling, and mood. Although psychiatric disorders place a large economic burden on society, the drugs available to treat them are often palliative with variable efficacy and intolerable side-effects. The development of novel drugs has been hindered by a lack of knowledge about the etiology of these diseases. It is thus necessary to further investigate psychiatric disorders using a combination of human molecular genetics, gene-by-environment studies, in vitro pharmacological and biochemistry experiments, animal models, and investigation of the non-biological basis of these diseases, such as environmental effects. Many psychiatric disorders, including autism spectrum disorder, attention-deficit/hyperactivity disorder, mental retardation, and schizophrenia can be triggered by alterations to neural development. The zebrafish is a popular model for developmental biology that is increasingly used to study human disease. Recent work has extended this approach to examine psychiatric disorders as well. However, since psychiatric disorders affect complex mental functions that might be human specific, it is not possible to fully model them in fish. In this review, I will propose that the suitability of zebrafish for developmental studies, and the genetic tools available to manipulate them, provide a powerful model to study the roles of genes that are linked to psychiatric disorders during neural development. The relative speed and ease of conducting experiments in zebrafish can be used to address two areas of future research: the contribution of environmental factors to disease onset, and screening for novel therapeutic compounds.
    Full-text · Article · Apr 2013 · Frontiers in Neural Circuits
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Summary and comment on a recent Disease Models & Mechanisms paper entitled ‘Mutation of zebrafish dihydrolipoamide branched-chain transacylase E2 results in motor dysfunction and models maple syrup urine disease’ (Friedrich et al., 2012).
    Full-text · Article · Jul 2012 · Disease Models and Mechanisms
  • [Show abstract] [Hide abstract]
    ABSTRACT: Animal models for studying human disease are essential to the continuing evolution of medicine. Rodent models are attractive for the obvious similarities in development and genetic makeup compared with humans, but have cost and technical limitations. The zebrafish (Danio rerio) represents an excellent alternative vertebrate model of human disease because of its high conservation of genetic information and physiological processes, inexpensive maintenance, and optical clarity facilitating direct observation. This review highlights recent advances in understanding genetic disease states associated with the dynamic organelle, the mitochondrion, using zebrafish. Mitochondrial diseases that have been replicated in the zebrafish include those affecting the nervous and cardiovascular systems, as well as red blood cell function. There are a large number of studies involving genes associated with Parkinson's disease, as well as many of the genes associated with heme synthesis and anemia. Gene silencing techniques, including morpholino knockdown and TAL-effector endonucleases have been exploited to demonstrate how loss of function can induce human diseaselike states in zebrafish. Moreover, modeling mitochondrial diseases has been facilitated greatly by the creation of transgenic fish with fluorescently labeled mitochondria for in vivo visualization of these structures. In addition, behavioral assays have been developed to examine changes in motor activity and sensory responses, particularly in larval stages. Zebrafish are poised to advance our understanding of the pathogenesis of human mitochondrial diseases beyond the current state of knowledge and provide a key tool in the development of novel therapeutic approaches to treat these conditions.
    No preview · Article · Sep 2013
Show more