Comparative Medical Genetics of Neuromuscular Diseases



Since January 1, 2015, our unit joined the Institut Mondor de Recherche Biomédicale (IMRB, Créteil, France) to form a larger, new team named "Biology of the neuromuscular system".
This team is codirected by Prof. F. Relaix & FJ. Authier.


Principal investigators

Fanny Pilot-Storck  DVM, Ph.D., HDR
Lucie Chevallier  DVM, Ph.D.
Laurent Tiret  DVM, Ph.D., HDR

Job offers

Presently (June 1, 2017), we are seeking for a Master student (M2). Information available on request by email.

Presentation     Personnel     Publications     Funding



The dog and cat models


Despite major efforts and a growing list of successes, identifying susceptibility genes for common diseases in human remains extremely difficult. This is likely due to the complexity of the underlying causes, including genetic and environmental heterogeneity, gene-by-gene and gene-by-environment interactions. In order to accelerate the discovery pace, studies that directly target human populations are therefore advantageously complemented by studies of more tractable animal models of human disease.


The dog and cat are relevant model systems to unravel the molecular basis of common diseases because they are exposed to the same environment as their owners and because each of the ~400 recognized breeds (in dogs) is a genetic isolate with unique characteristics (Lindblad-Toh et al., 2005. Nature; Ostrander, 2012. The NEJM). Over 500 genetic diseases have been reported in dogs and cats, and comparative pathophysiology showed that histopathological features, genes and pathways are likely to be similar between humans, dogs and cats.


Because their size is closer to that of the baby or adult human, the cat and dog are also considered to be superior model systems when compared to rodent models for the development of strategies for gene therapy. The shorter lifespan of dogs and cats when compared to humans suggests that clinical trials can be conclusively completed in a much shorter time span than human trials.


The Alfort School in France is a major European veterinary clinic (~30,000 cases per year; more info on the ChuvA) and our laboratory collects DNAs from dogs and cats that are thoroughly phenotyped by board-certified specialized veterinarians.

Mapping disease genes


Using linkage or genome-wide/rare variant association studies (GW/RV-AS) combined with candidate gene or massive parallele whole-genome sequencing (NGS), we identified causative gene mutations accounting for phenotypic traits including hair coat color and structure or muscular and neurological disorders. In particular, recessive mutations in the protein tyrosine phosphatase-like, member A (PTPLA/HACD1), the arylsulfatase G (ARSG) and the forkhead box N1 (FOXN1) genes have been characterized and lead respectively to a myopathy in the Labrador retriever [Pelé et al., 2005; Maurer et al., 2012], a neuronal ceroid lipofuscinosis in the American Staffordshire Terrier [Abitbol et al., 2010] and a congenital hypotrichosis and short life expectancy syndrome in Birman cats [Abitbol et al., 2015]. Using a candidate gene approach, we also contributed to identify and characterize mutations in the myotubularin (MTM1) and the BIN1 gene leading to a myopathy in the Labrador retriever or the great Dane [Beggs et al., 2010 ; Böhm et al., 2013].   


Besides, we have been involved (2008-2012) in the LUPA large-scale integrating project associating veterinary campuses from 12 European countries, which aimed to unravel the molecular basis of common complex human disorders using the dog as a model system. We have been particularly interested in the genetic determinants of variation in blood pressure, glucose and lipid metabolism and natriuretic peptides in healthy dogs [Sjöstrand et al., 2014; Forsberg et al., 2015]. Projects focusing on hereditary disorders in cats are also developed and are part of a national network named Cani-DNA, and funded by an "Investissement d'avenir" through the development of the CRB-Anim Biological Resources Centre.

HACD genes, very-long chain fatty acids (VLCFA) and centronuclear myopathies (CNM)


We initially identified a loss-of-function mutation in the HACD1/PTPLA gene, causing an autosomal recessive form of CNM in Labrador retrievers [Pelé et al., 2005] worldwide [Maurer et al. 2012]. CNM form a group of rare disorders, characterized by muscle atrophy, hypotonia and locomotor weakness. Histological hallmarks include size heterogeneity, cytoplasmic disorganization and progressive nuclear centralization [Tiret et al., 2003].


HACD1 has recently been identified as a key 3-hydroxyacyl-CoA dehydratase of the endoplasmic reticulum, involved in the elongation of very long chain fatty acids (VLCFA), i.e. fatty acids containing 20 carbons or more [Denic et al., 2007. Cell; Ikeda et al., 2008. FEBS Letters; Kihara et al., 2008. J Biol Chem]. We thus investigated how HACD1, through VLCFA, controls muscle fiber architecture and growth and identified that VLCFA confer unique structural and functional properties to membranes; they are also sphingolipids components, which constitute specialized membrane domains called lipid rafts. These domains are important modulators of signaling and trafficking pathways. Using myoblasts C2C12 cell lines knocked down for Hacd1, Hacd1 knockout mice and knockdown dogs, we analyzed the roles of HACD1 and VLCFA at the organism, tissular, cellular and molecular levels through lipidomics and proteomics analyses and unraveled that Hacd1 promotes myoblast fusion and muscle growth [Blondelle et al., 2015].
That HACD1 is essential to muscle homeostasis has been recently strengthened by the identification in a Bedouin consanguineous family of a loss-of-lunction HACD1 allele, leading to a severe congenital myopathy [Muhammad et al., 2013].

Presently, we also aim at unraveling the functional interactions of HACD1 with proteins involved in human X-linked and autosomal forms of CNM, such as MTM1, DNM2 and BIN1.


In vivo, VLCFA synthesis in HACD1-deficient conditions can be rescued by Hacd2, the closest Hacd1 paralog. A complementary present project is thus to investigate the functional consequences of a targeted deletion in Hacd2, or in both Hacd1 and Hacd2 (double knockout mutants) in mouse embryos and adults. Phenotyping these mutants will reveal organs in which HACD1/2-dependent VLCFA synthesis is essential.


Present members

  • Laurent Tiret, permanent professor, PI

  • Fanny Pilot-Storck, permanent associate professor, PI (Function of Hacd genes)

  • Lucie Chevallier, permanent assistant professor (Animal genetics, Cani-DNA)

  • Philippe Bossé, permanent professor (Companion animal genetics)

  • Edouard Reyes-Gomez, permanent assistant professor (Rhabdomyosarcoma)

  • Alexandre Prola, postdoc (Hacd1 gene in metabolism)

  • Ambre Jaraud-Darnault, DVM & research engineer (Cani-DNA & CRB-Anim)

  • Nahed Khadhraoui, PhD student (Hacd2 gene function)

  • Aymeline Vandestienne, PhD student (Hacd1 gene in metabolism)


  • Laurent Guillaud, permanent technician (CNM & Hacd genes projects)

  • Guillaume Courtin, assistant engineer (Hacd genes project)

  • Camille Laisne & Diana Gelperowic (technician and assistant; mouse facilities)

Past members

  • Marie Abitbol, 12-year stay (2005-2016), assistant professor in Molecular and Medical Genetics. Marie is now at the VetAgro Sup school in Lyon, France.

  • Nahed Khadhraoui 10-month stay (2014-2015), Master student M2 (ReproDev)

  • Vincent Gache 9-month stay (2014). Postdoc, recruited in May 2014 as a permanent researcher (CR2) by Inserm. Vincent  joined Laurent Schaeffer's lab in Lyon, France, in October 2014

  • Anaëlle Rahier (2014), Master student M1 from AgroParisTech

  • Jordan Blondelle (2010-2013), Ph.D. student from Université Paris 7. Jordan is now a postdoc in Stephen Lange lab, UC San Diego, USA.

  • Maxime Bodak, 7-month stay (2013). Master student M2 from Université Paris 7. Maxime is now a PhD student in Constance Ciaudo lab, Zürich, Switzerland.

  • Marie Maurer (2011). Engineer. Marie is now a postdoc in Sonia Berrih-Aknin & Rozen Le Panse lab, Institut de myologie, Paris, France.

  • Léna Vouillot, 6-month stay (2011). Engineer

  • Romain Bidanel, 7-week stay (2011). Student in higher technician certificate

  • Emilie Filhol (2010). Master student M2

  • Marie Maurer (2007-2010). Ph.D. student

  • Vasiliki Gkouni (2008-2009). Veterinarian cardiologist

  • Jérôme Mary (2006-2009). Ph.D. student

  • Jean-Louis Kessler (1992-2009). Technician

  • Carole Drougard (2008). Engineer

  • Manuel Pelé (2001-2006). Master student M2 and Ph.D. student


  • and short- or mid-term training courses for students in veterinary medicine and other scientific fields:

2015 - Adrien Da Silva, Maellys Kevin, Amélie Tuton, Camille Roux, Marion Davidson
2014 -
Camille Roux, Romain Legrand, Marion Davidson, Michaël Martineau, Alexandre Guyonvarch, Olivier Postal, Clémentine Escouflaire
2013 - Romain Legrand
2012 - Fabien Descrouet, Myriam Taleb, Renaud Fouchère, Charles Guingouain
2011 - Souheyla Benfrid, Fabien Descrouet, Myriam Taleb, Renaud Fouchère, Alice Balard
2010 - Alexia Hamelin
2009 - Jean-Charles Husson

Publications by members from the team (bolded)

  • Abitbol M., Hitte C., Bossé P., Blanchard-Gutton N., Thomas A., Martignat L., Blot S., Tiret L. (2015).
    A COLQ Missense Mutation in Sphynx and Devon Rex Cats with Congenital Myasthenic Syndrome. PLoS ONE 10, e0137019.


  • Blondelle, J., Ohno, Y., Gache, V., Guyot, S., Storck, S., Blanchard-Gutton, N., Barthélémy, I., Walmsley, G., Rahier, A., Gadin, S., Maurer, M., Guillaud, L., Prola, A., Ferry, A., Aubin-Houzelstein, G., Demarquoy, J., Relaix, F., Piercy, R.J., Blot, S., Kihara, A., Tiret, L. & Pilot-Storck, F. (2015).
    HACD1, a regulator of membrane composition and fluidity, promotes myoblast fusion and skeletal muscle growth. J Mol Cell Biol. in press.


  • Forsberg, S.K.G., Kierczak, M., Ljungvall, I., Merveille, A.-C., Gouni, V., Wiberg, M., Lundgren Willesen, J., Hanås, S., Lequarré, A.-S., Mejer Sørensen, L., Tiret, L., McEntee, K., Seppälä, E., Koch, J., Battaille, G., Lohi, H., Fredholm, M., Chetboul, V., Häggström, J., Carlborg, Ö., Lindblad-Toh, K. & Höglund, K. (2015).
    The Shepherds’ Tale: A Genome-Wide Study across 9 Dog Breeds Implicates Two Loci in the Regulation of Fructosamine Serum Concentration in Belgian Shepherds. PLoS ONE 10, e0123173.


  • Abitbol M, Legrand R, Tiret L. (2015)
    A missense mutation in the agouti signaling protein gene (ASIP) is associated with the no light points coat phenotype in donkeys. Genet Sel Evol. 47(1):28.


  • Abitbol M, Bossé P, Thomas A, Tiret L. (2015)
    A Deletion in FOXN1 Is Associated with a Syndrome Characterized by Congenital Hypotrichosis and Short Life Expectancy in Birman Cats. PLoS ONE 10(3):e0120668.
  • Legrand R, Tiret L, Abitbol M. (2014)
    Two recessive mutations in FGF5 are associated with the longhair phenotype in donkeys. Genet Sel Evol. 46(1):65.


  • Abitbol M, Legrand R, Tiret L. (2014)
    A missense mutation in melanocortin 1 receptor is associated with the red coat colour in donkeys. Anim Genet. 2014. 45(6):878-880.


  • Sjöstrand K., Wess G., Ljungvall I., Häggström J., Merveille A.C., Wiberg M., Gouni V., Lundgren-Willesen J., Hanås S., Lequarré A.S., Meyer-Sorensen L., Wolf J., Tiret L., Kierczak M., Forsberg S., McEntee K., Bataille G., Seppälä E., Lindblad-Toh K., Georges M., Lohi H., Chetboul V., Fredholm M., Höglund K. (2014).
    Breed differences in natriuretic peptides in healthy dogs. The J Vet Intern Medicine. 28(2):451-457.


  • Piazza S, Abitbol M, Gnirs K, Huynh M, Cauzinille L. (2014).
    Prevalence of deafness and association with coat variations in client-owned ferrets. J Am Vet Med Assoc. 244(9):1047-52.


  • Böhm J., Vasli N., Maurer M., Cowling B., Shelton G.D., Kress W., Toussaint A., Prokic I., Schara U., Anderson J., Herrmann R., Weis J., Tiret L., Laporte J. (2013).
    Altered Splicing of the BIN1 Muscle-Specific Exon in Humans and Dogs with Highly Progressive Centronuclear Myopathy. PLoS Genet, 9(6): e1003430
  • Read the comment in ScienceNOW


  • Borensztein M., Louault Y., Court F., Ripoche M.A., Tiret L., Yao Z., Tapscott S.J., Forné T., Montarras D., Dandolo L. (2013).
    Myod and H19-Igf2 locus interactions are required for diaphragm formation in the mouse. Development. 140(6): 1231-9.


  • Chetboul V., Petit A., Gouni V., Trehiou-Sechi E., Misbach C., Balouka D., Carlos Sampedrano C., Pouchelon J.L., Tissier R., Abitbol M. (2012).
    Prospective echocardiographic and doppler screening of a large Sphynx cat population: reference ranges, heart disease prevalence and genetic aspects. J Vet Cardiol.  14(4):497-509.


  • 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 7, e46408.


  • Baas D., Caussanel-Boude S., Guiraud A., Calhabeu F., Delaune E., Pilot F., Chopin E., Machuca-Gayet I., Vernay A., Bertrand S., Rual J.F., Jurdic P., Hill D.E., Vidal M., Schaeffer L., Goillot E. (2012).
    CKIP-1 regulates mammalian and zebrafish myoblast fusion. J Cell Sci.  125, 3790-3800.


  • Vaysse A., Ratnakumar A., Derrien T., Axelsson E., Rosengren Pielberg G., Sigurdsson S., Fall T., Seppälä E.H., Hansen M.S.T., Lawley C.T., Karlsson E.K., The LUPA Consortium, Bannasch D., Vilà C., Lohi H., Galibert F., Fredholm M., Häggström J., Hedhammar Å., André C., Lindblad-Toh K., Hitte C., Webster M.T. (2011).
    Identification of Genomic Regions Associated with Phenotypic Variation between Dog Breeds using Selection Mapping. PLoS Genet. 7, e1002316-e1002316. Read the article


  • Lyoumi S., Abitbol M., Rainteau D., Karim Z., Bernex F., Oustric V., Millot S., Letteron P., Heming N., Guillmot L., Montagutelli X., Berdeaux G., Gouya L., Poupon R., Deybach J.C., Beaumont C., Puy H. (2011).
    Protoporphyrin retention in hepatocytes and Kupffer cells prevents sclerosing cholangitis in erythropoietic protoporphyria mouse model. Gastroenterology. 141, 1509-1519.


  • Abitbol, M., Thibaud, J.L., Olby, N.J., Hitte, C., Puech, J.P., Maurer, M., Pilot-Storck, F., Hedan, B., Dreano, S., Brahimi, S., Delattre, D., Andre, C., Gray, F., Delisle, F., Caillaud, C., Bernex, F., Panthier, J.J., Aubin-Houzelstein, G., Blot, S. and Tiret, L. (2010)
    A canine Arylsulfatase G (ARSG) mutation leading to a sulfatase deficiency is associated with neuronal ceroid lipofuscinosis. Proc. Natl. Acad. Sci. U. S. A., 107, 14775-80. Read the article


  • Beggs, A.H., Bohm, J., Snead, E., Kozlowski, M., Maurer, M., Minor, K., Childers, M.K., Taylor, S.M., Hitte, C., Mickelson, J.R., Guo, L.T., Mizisin, A.P., Buj-Bello, A., Tiret, L., Laporte, J. and Shelton, G.D. (2010)
    MTM1 mutation associated with X-linked myotubular myopathy in Labrador Retrievers. Proc. Natl. Acad. Sci. U. S. A., 107, 14697-702. Read the article


  • Pilot-Storck, F., Chopin, E., Rual, J.F., Baudot, A., Dobrokhotov, P., Robinson-Rechavi, M., Brun, C., Cusick, M.E., Hill, D.E., Schaeffer, L., Vidal, M. and Goillot, E. (2010)
    Interactome mapping of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway identifies deformed epidermal autoregulatory factor-1 as a new glycogen synthase kinase-3 interactor. Mol. Cell. Proteomics, 9, 1578-93.


  • Mary, J., Chetboul, V., Sampedrano, C.C., Abitbol, M., Gouni, V., Trehiou-Sechi, E., Tissier, R., Queney, G., Pouchelon, J.L. and Thomas, A. (2010)
    Prevalence of the MYBPC3-A31P mutation in a large European feline population and association with hypertrophic cardiomyopathy in the Maine Coon breed. J. Vet. Cardiol., 12, 155-61.


  • Maurer, M. and Tiret, L. (2009)
    Histoire évolutive du Chien et des races revisitée par la génomique. In Deputte, T.B.B. (ed.), Comportement et éducation du chien. Educagri, Paris, pp. 301-314.


  • Pelé, M., Tiret, L., Kessler, J.L., Blot, S. and Panthier, J.J. (2005)
    SINE exonic insertion in the PTPLA gene leads to multiple splicing defects and segregates with the autosomal recessive centronuclear myopathy in dog. Hum. Mol. Genet., 14, 1417-1427. Read the abstract


  • Tiret, L., Blot, S., Kessler, J.L., Gaillot, H., Breen, M. and Panthier, J.J. (2003)
    The cnm locus, a canine homologue of human autosomal forms of centronuclear myopathy, maps to chromosome 2. Hum. Genet., 113, 297-306.


  • Tiret, L., Kessler, J.L., Bentolila, S., Faure, S., Bach, J.M., Weissenbach, J. and Panthier, J.J. (2000)
    Assignation of highly polymorphic markers on a canine purebred pedigree. Mamm. Genome, 11, 703-5.


  • Tiret, L., Kessler, J.L., Bentolila, S., Faure, S., Bach, J.M., Weissenbach, J. and Panthier, J.J. (1999)
    Characterization and mapping of canine polymorphic markers. Anim. Genet., 30, 475-6.


GFM_Funding 2013