ISTM

Laboratory-based research since 1999 on the biochemistry and cell biology of inherited neuromuscular disease. Currently leading Monoclonal Antibody and Confocal Microscopy Research at the Wolfson Centre for Inherited Neuromuscular Disease (Research Director: Prof Glenn Morris). Our main aim is to produce highly specific monoclonal antibodies and to apply these antibodies ourselves and in collaboration with others, to research the pathogenesis of neuromuscular disease, to investigate potential therapies and to use as diagnostic tools and for monitoring clinical trials. Current project is the functions and roles of nesprin proteins in the pathogenesis of inherited cardiomyopathy. Other projects included myotonic dystrophy, Emery-Dreifuss muscular dystrophy and congenital muscular dystrophies, working with a large network of national and international scientific and clinical collaborators. Recent collaborators include groups in London, Nottingham, Glasgow, France, Holland, Germany, USA and Canada.

Earlier experience included research into metabolic bone disease (PhD, University of Manchester) and Rheumatology (MSc, University of Manchester).

ISTM research theme: Bioengineering and Therapeutics

Main Research Interests:

• Nesprin Isoforms and Variants: their Functions and Roles in the Pathogenesis of Inherited Cardiomyopathy.
• Myotonic dystrophy.
• Emery-Dreifuss muscular dystrophy.

Other Information:

Associate Editor of “Translational Neuroscience” since 2010.

Journal and Book Chapter Publications since 2001:

Sewry CA, Quinlivan RCM, Squier W, Morris GE and Holt I. (2012) A rapid immunohistochemical test to distinguish congenital myotonic dystrophy from X-linked myotubular myopathy. Neuromuscular Disorders 22(3):225-230.

Paul S, Dansithong W, Jog SP, Holt I, Mittal S, Brook JD, Morris GE, Comai L and Reddy S. (2011) Expanded CUG repeats dysregulate RNA splicing by altering the stoichiometry of the muscleblind 1 complex. Journal of Biological Chemistry 286(44):38427-38438.

Holt I and Pham YCN (2011). Nucleic acid polymers and applications of recombinant DNA technology. In: RSC Polymer Chemistry Series 1(Chapter 14):399-429. Renewable resources for functional polymers and biomaterials (Editor: Williams PA). Royal Society of Chemistry, Cambridge UK.

Holt I, Lam LT, Tomé S, Wansink DG, Te Riele H, Gourdon G and Morris GE (2011). The mouse mismatch repair protein, MSH3, is a nucleoplasmic protein that aggregates into denser nuclear bodies under conditions of stress. Journal of Cellular Biochemistry 112(6):1612-1621.

Tran H, Gourrier N, Lemercier-Neuillet C, Dhaenens CM, Vautrin A, Fernandez-Gomez FJ, Arandel L, Carpentier C, Obriot H, Eddarkaoui S, Delattre L, Van Brussels E, Holt I, Morris GE, Sablonnière B, Buée L, Charlet-Berguerand N, Schraen-Maschke S, Furling D, Behm-Ansmant I, Branlant C, Caillet-Boudin ML and Sergeant N (2011). Analysis of exonic regions involved in nuclear localization, splicing activity, and dimerization of muscleblind-like-1 isoforms. Journal of Biological Chemistry 286(18):16435-16446.

Wielders EA, Dekker RJ, Holt I, Morris GE and Te Riele H (2011). Characterization of MSH2 variants by endogenous gene modification in mouse embryonic stem cells. Human Mutation 32(4):389-396.

Holt I, Quinlivan RCM, Couto JM, Monckton DG and Morris GE (2010). The use of buccal cells for rapid diagnosis of myotonic dystrophy type 1. Translational Neuroscience 1(3) 195-199.

Mladinov M, Mayer D, Br?i? L, Wolstencroft E, Man NT, Holt I, Hof PR, Morris GE and Šimi? G (2010). Astrocyte expression of D2-like dopamine receptors in the prefrontal cortex. Translational Neuroscience 1(3) 238-243.

Holt I, Jacquemin V, Fardaei M, Sewry CA, Butler-Browne GS, Furling D, Brook JD and Morris GE (2009). Muscleblind-like proteins: similarities and differences in normal and myotonic dystrophy muscle. American Journal of Pathology 174(1):216-227.

Tomé S, Holt I, Edelmann W, Morris GE, Munnich A, Pearson CE and Gourdon G (2009). MSH2 ATPase domain mutation affects CTG*CAG repeat instability in transgenic mice. PLoS Genetics 5(5):e1000482.

Dansithong W, Wolf CM, Sarkar P, Paul S, Chiang A, Holt I, Morris GE, Branco D, Sherwood MC, Comai L, Berul CI and Reddy S (2008). Cytoplasmic CUG RNA Foci Are Insufficient to Elicit Key DM1 Features. PLoS ONE 3(12):e3968.

Holt I, Mittal S, Furling D, Butler-Browne GS, Brook JD and Morris GE (2007). Defective mRNA in myotonic dystrophy accumulates at the periphery of nuclear splicing speckles. Genes to Cells 12:1035-1048.

Wolstencroft EC, Simic G, Nguyen TM, Holt I, Le TL, Buckland PR and Morris GE (2007). Endosomal location of dopamine receptors in neuronal cell cytoplasm. Journal of Molecular Histology 38:333-340. 3

Holt I, Nguyen TM, Wehnert M and Morris GE (2006). Lamin A/C assembly defects in Emery-Dreifuss muscular dystrophy can be regulated by culture medium composition. Neuromuscular Disorders 16:368-373.

Pham YCN, Nguyen TM, Holt I, Sewry CA, Pall G, Johnson K and Morris GE (2005). Characterisation of the transcription factor, SIX5, using a new panel of monoclonal antibodies. Journal of Cellular Biochemistry 95:990-1001.

Holt I, Östlund C, Stewart CL, Nguyen TM, Worman HJ and Morris GE (2003). The effect of pathogenic missense mutations in lamin A on its interaction with emerin in vivo. Journal of Cell Science 116:3027-3035.

Wilkinson FL, Holaska JM, Zhang Z, Sharma A, Manilal S, Holt I, Stamm S, Wilson K and Morris GE (2003). Emerin interacts in vitro with the splicing-associated factor, YT521-B. European Journal of Biochemistry 270:2459-2466.

Morris GE, Manilal S, Holt I, Tunnah D, Clements L, Wilkinson FL, Sewry CA and Nguyen TM. (2002). The distribution of emerin and lamins in X-linked Emery-Dreifuss muscular dystrophy. In: Molecular Biology Intelligence Unit 23:143-151. Kluwer Academic Publishers.

Holt I, Clements L, Manilal S and Morris GE (2001). How does a g993t mutation in the emerin gene cause Emery-Dreifuss muscular dystrophy? Biochemical and Biophysical Research Communications 287:1129-1133.

Holt I, Clements L, Manilal S, Brown SC and Morris GE (2001). The R482Q lamin A/C mutation that causes lipodystrophy does not prevent nuclear targeting of lamin A in adipocytes or its interaction with emerin. European Journal of Human Genetics 9:204-208.

Research Impacts (Lay Summary):

Over 70,000 people in the UK alone are living with a serious neuromuscular condition, many of them are young children and at present there are usually no effective treatments.

Myotonic dystrophy is the most common form of muscular dystrophy in adults but it is especially distressing for parents when a baby is born with congenital myotonic dystrophy. These babies are often born prematurely. Those that survive are often floppy and weak, with difficulty with sucking, swallowing and breathing. Working with the Great Ormond Street Children’s Hospital, we have developed a rapid and non-invasive diagnostic test for myotonic dystrophy in floppy babies based on antibodies produced in Oswestry. Other antibodies from Oswestry (anti-MSH3) will be used by international collaborators to search for drugs that will directly reduce the genetic defect in myotonic dystrophy patients, as well as novel anti-cancer drugs. We are also participating in an international effort to improve diagnostic tests for congenital muscular dystrophies using new antibodies.

The British Heart Foundation is also supporting us to produce new antibodies that will help researchers understand both serious heart disease (cardiomyopathy) and the very common minor heart perturbations (conduction defects) that affect a large proportion of the UK population.