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

Abstract

SUMMARYAnalysis 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.

Maple Syrup Urine Disease

“…40 BCKDC activity was found to be 5-6% of normal, but was sufficient to allow the animals to survive. [43][44][45][46] Recent studies by Friedich et al 47 revisited the known que mutation associated with abnormal postfertilization muscle contraction, and determined that it is a single-point mutation within the E2 gene. We have since added additional amino acids to the full-length E2 monomers and this extension also results in trimer formation (Wynn et al, unpublished results).…”

Escape trajectories are deflected when fish larvae intercept their own C-start wake

“…During the 158 turn (from [29], figure 3), the larva was touched at the tail (figure 9a) and started a forward escape. During the 1408 turn (from [38], figure 1a), the fish was touched at the snout (figure 9b) and turned to swim away from the threat. In the 1408 turn, the body bent so that the tail ended up underneath the head at the end of stage 1 ( figure 9c).…”

“…We used the centre-of-mass (CoM) kinematics of the recorded zebrafish to validate our computational model ( §3.1) and quantified the flow pattern focusing on the wake interception ( §3.2). We explore the effect of wake interception by comparing the factual simulation with counterfactual simulations without wake interception in §3.3 and discuss escape trajectory affects wake interception and vice versa in larval fish [29,38] in §3.4. The effect of Reynolds number on the turning angle of the head and the nature of the wake interception is discussed in §3.5.…”

Toward developmental models of psychiatric disorders in zebrafish

“…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.…”