A spotlight on HACD1-associated congenital myopathies

Dr Gemma Walmsley (left) is a senior lecturer and specialist in veterinary neurology at the University of Liverpool. She has been researching HACD1-associated CNM since 2009 when she completed her PhD, funded by the Myotubular Trust, at the Royal Veterinary College. Since moving to Liverpool, she was joined by Dr Rhiannon Morgan (right) in 2015 when she began her PhD studies on HACD1 in zebrafish embryos. They recently received a grant award for their work from The National Centre for the Replacement Refinement and Reduction of Animals in Research (NC3Rs). The award aims to replace the use of dogs and mice in studies of congenital muscle disorders by developing an early stage zebrafish embryo model deficient in HACD1.

HACD1 is a protein involved in elongating the chains of fatty acids. When the HACD1 gene is mutated, this causes centronuclear myopathy (CNM) in Labrador Retrievers and affected dogs have a centronuclear myopathy with many classical features including muscle hypotrophy, centralisation of myonuclei (Figure 1) (Maurer et al., 2012, Walmsley et al., 2017). More recently HACD1 mutations have also been documented in two human families with congenital myopathies (Muhammed et al., 2013; Toscano et al., 2017).

Figure 1: (A&B) Two Labradors from the same litter: (A) a healthy, non-affected Labrador and (B) a HACD1-CNM affected Labrador. The affected dog is unable to hold himself up properly due to weakness. Canine muscle biopsy of both (C) healthy canine annotated with black arrows pointing to the nuclei, and (D) CNM affected muscle biopsy with black arrows annotating the nuclei that have become centralised.

Researchers at the University of Liverpool and collaborators in Manchester and Paris have now been awarded funding from the National Centre for Replacement Refinement and Reduction of Animals in Research (NC3Rs) to generate a novel congenital myopathy model in embryonic zebrafish with HACD1-deficiency.

Zebrafish embryos develop their muscle within the first three days of fertilisation and have been used by a number of other research groups to model other forms of CNM (Dowling et al., 2009, Smith et al., 2014). Using the HACD1 mutant model, they will specifically investigate muscle structure, muscle function and lipid composition in HACD1 mutant embryos to improve understanding of the pathogenesis of the condition and hopefully aid the development of treatments that could help this and other forms of CNM in dogs and humans.

Further information

Further information about this project can be found below.


Dowling, J. J., Vreede, A. P., Low, S. E., Gibbs, E. M., Kuwada, J. Y., Bonnemann, C. G. & Feldman, E. L. (2009). Loss of myotubularin function results in T-tubule disorganization in zebrafish and human myotubular myopathy. PLoS Genetics.

Maurer, M., Mary, J., Guillaud, L., Fender, M., Pelé, M., Bilzer, T., Olby, N., Penderis, J., Shelton, G. D., Panthier, J.-J., Thibaud, J.-L., Barthélémy, I., Aubin-Houzelstein, G., Blot, S., Hitte, C. & Tiret, L. 2012. Centronuclear Myopathy in Labrador Retrievers: A Recent Founder Mutation in the PTPLA Gene Has Rapidly Disseminated Worldwide. PLOS ONE.

Muhammad, E., Reish, O., Ohno, Y., Scheetz, T., Deluca, A., Searby, C., Regev, M., Benyamini, L., Fellig, Y., Kihara, A., Sheffield, V. C. & Parvari, R. 2013. Congenital myopathy is caused by mutation of HACD1. Hum Mol Genet.

Smith, L. L., Gupta, V. A. & Beggs, A. H. 2014. Bridging integrator 1 (Bin1) deficiency in zebrafish results in centronuclear myopathy. Human Molecular Genetics.

Toscano, A., Emmanuele, V., Savarese, M., Musumeci, O., Torella, A., Conca, E., Moggio, M., Nigro, V. & Rodolico, C. 2017. Pseudo-dominant inheritance of a novel homozygous HACD1 mutation associated with congenital myopathy: The first caucasian family. Neuromuscular Disorders.

Walmsley, G. L., Blot, S., Venner, K., Sewry, C., Laporte, J., Blondelle, J., Barthelemy, I., Maurer, M., Blanchard-Gutton, N., Pilot-Storck, F., Tiret, L. & Piercy, R. J. 2017. Progressive Structural Defects in Canine Centronuclear Myopathy Indicate a Role for HACD1 in Maintaining Skeletal Muscle Membrane Systems. Am J Pathol, 187(2), pp 441-456.

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