Neuromuscular Diseases

The Laing Laboratory is one of the world's foremost laboratories in the investigation of the genetic causes of muscle diseases in newborn children. The Laboratory was the first in the world to identify a gene for one sub-group of these disorders and later showed that many of the children affected with these diseases have mutations in one of the two most important proteins in muscle contraction. These results have helped families all round the world know the cause of their children's muscle problems. We are now researching possible treatments for diseases where we have identified the genes, while at the same time continuing work to find other genes for muscle diseases. The Laboratory's reputation means that we receive samples for analysis from all round the world. The Laboratory is thus playing a leading role in a consortium of groups working towards defeating these diseases.

In 2008, Professor Laing, edited the first ever book on the human muscle diseases caused by mutations in the proteins of the sarcomere, the functional unit of muscle contraction. This reinforces the standing of the Laing Laboratory in researching and pioneering this group of diseases.

Senior Research Staff

Professor Nigel Laing Head, Neuromuscular Diseases Research: genetic muscular disorders	A/Professor Kristen Nowak Fellow Research: neuromuscular disease genetics; actin proteins; recombinant protein production
Dr Gina Ravenscroft Research Associate Research: genetic muscular disorders	Dr Rachael Duff Research Associate Research: genetic muscular disorders

Research Details

The Laing Laboratory has been hunting human disease genes for nearly twenty years. We started analysing large Australian families with dominantly inherited neurological and neuromuscular disorders, making world first discoveries. These discoveries led to DNA samples being sent to us from around the world for the diseases that we had identified genes for and this continuing influx of samples in turn has led to further breakthroughs.

The fact is that in Australasia there are many large families with dominant diseases because of founder effects, where one person carrying a dominant mutation has emigrated to Australia, stayed in this wonderful country and had large families, with many descendents that we can trace. In order to find the genes for dominant human diseases, you have to study large families, so it follows that in many ways Australia is an ideal country in which to study dominant diseases. It also means that we are able to carry out studies that other groups around the world cannot. This has allowed us over the years to break new ground. As an example, Western Australia has one of the largest inherited familial amyotrophic lateral sclerosis (FALS) (otherwise known as motor neurone disease) families in the world. This family helped identify what is still the major gene identified for FALS, the superoxide dismutase gene (SOD1) in 1993.

We simultaneously were working on the largest known family with dominantly inherited nemaline myopathy, one of the better known congenital myopathies, diseases which generally affect newborn babies and at there most severe lead to complete paralysis at birth. We obtained the first linkage of a gene for nemaline myopathy to a region of chromosome 1 in this family in 1992 and three years later in 1995 identified the first gene found for nemaline myopathy as mutated slow alpha-tropomyosin (TPM3), one of the muscle thin filament proteins. This discovery created a paradigm shift in our understanding of this group of diseases.

In 1995 we also obtained the first ever linkage for any distal myopathy, this time in a large Western Australian family. This family has an unusual form of distal myopathy in that it has childhood onset, whereas most dominant distal myopathies have adult onset. In 2004 we finally published that the gene was mutated slow-skeletal/beta-cardiac myosin (MYH7), which was a huge surprise to the muscle research community since mutations in this gene had already been associated with cardiomyopathy. However, it is now perfectly clear that particular mutations in a particular region of that myosin cause this relatively skeletal-muscle specific disease, yet other mutations in the gene cause the skeletal muscle disease myosin storage myopathy, while most mutations in the gene cause cardiomyopathy. This work adds to the growing understanding that different mutations in one gene can cause different diseases.

In 1999 the Laing Laboratory identified, for the first time, mutations in the skeletal muscle alpha-actin gene (ACTA1) as a cause of congenital myopathies. This initial publication described 15 different mutations in ACTA1 causing nemaline myopathy, intranuclear rods and accumulation of actin in muscle fibres. We now know that mutations in ACTA1 may also cause congenital fibre type disproportion and core-like phenotypes and so far we, and others, have found over 130 different mutations in ACTA1.

The Laing laboratory has thus coincidentally identified human muscle diseases of the two most fundamental proteins in muscle contraction - actin and myosin. Our most recent finding is recessive ACTA1 disease causing complete absence of skeletal muscle actin. Interestingly, most of the affected children have some movement at birth and our studies show that the level of function in the children likely correlates with how much alpha-cardiac actin the children are expressing in their muscles. Cardiac alpha-actin is the fetal isoform of actin, normally present in developing muscle, but switched off around birth. The children with no alpha-skeletal actin have maintained variable levels of this fetal actin.

One of the puzzles with children severely affected by mutations in the skeletal muscle alpha actin gene ACTA1 is that eye movements remain unaffected even when other skeletal muscles are barely functional. In 2008 we showed that the extraocular muscles, the muscles that move the eyes, have high levels of cardiac actin, similar levels in fact to those in the heart. We postulated that it is this high level of cardiac actin that maintains function in the eye muscles.

Way back when we first found skeletal muscle actin disease in 1998, we wondered whether it would be possible to use cardiac actin, the actin isoform present in fetal muscle, to treat skeletal muscle actin disease. We set out to see how well cardiac actin might function in skeletal muscle. In collaboration with Professor Dame Kay Davies in Oxford, Dr Kristen Nowak made the transgenic mice that express high levels of cardiac actin in skeletal muscle necessary to test this. We imported those mice back to Australia and also mice from the laboratory of Professor Jim Lessard in the USA in which he had knocked out the skeletal muscle actin gene. Homozygous skeletal muscle actin knockout mice, mice with both copies of their skeletal actin gene knocked out died by nine days after birth. If cardiac actin could replace skeletal muscle actin in muscles after birth, if we bred the cardiac actin mice from Oxford with the skeletal actin knockout mice from the USA, then the resulting mice would survive. This is exactly what happened. The offspring mice were very similar to normal mice and have managed to live past two years of age, which is old age for mice. This work was published online in the Journal of Cell Biology May 25th 2009 (http://jcb.rupress.org/pap.shtml).

Having identified a number of disease genes, our aims now are to continue finding other human disease genes, decipher the mechanisms of pathobiology caused by the mutant proteins, while at the same time working towards developing treatments for some of these diseases.

Group Highlights

The Laing Laboratory's main funding is from the Australian National Health and Medical Research Council (NH&MRC). The Laboratory also regularly receives funding from the US Muscular Dystrophy Association (USMDA) and the Association Francaise contre les Myopathies (AFM) the French Muscular Dystrophy Association and is supported by the Western Australian Government's Medical and Health Research Infrastructure Fund.

Professor Laing is an NHMRC Principal Research Fellow.

2010 Publications

1. Kiphuth IC, Neuen-Jacob E, Struffert T, Wehner M, Wallefeld W, Laing N, Schroder R. 2010. Myosin storage myopathy: a rare subtype of protein aggregate myopathies. Fortschritte der Neurologie-Psychiatrie 78:219-222. [NCBI PubMed Entry]
2. Seenarain V, Viola HM, Ravenscroft G, Casey TM, Lipscombe RJ, Ingley E, Laing NG, Bringans SD, Hool LC. 2010. Evidence of altered guinea pig ventricular cardiomyocyte protein expression and growth in response to a 5 min in vitro exposure to H(2)O(2). Journal of Proteome Research 9:1985-1994. [NCBI PubMed Entry]
3. Stenzel W, Prokop S, Kress W, Huppmann S, Loui A, Sarioglu NM, Laing NG, Sparrow JC, Heppner FL, Goebel HH. 2010. Fetal akinesia caused by a novel actin filament aggregate myopathy skeletal muscle actin gene (ACTA1) mutation. Neuromuscular disorders 20:531-533. [NCBI PubMed Entry]
4. Copeland O, Nowak KJ, Laing NG, Ravenscroft G, Messer AE, Bayliss CR, Marston SB. 2010. Investigation of changes in skeletal muscle alpha-actin expression in normal and pathological human and mouse hearts. Journal of muscle research and cell motility 31(3):207-214. [NCBI PubMed Entry]
5. Song W, Dyer E, Stuckey D, Leung MC, Memo M, Mansfield C, Ferenczi M, Liu K, Redwood C, Nowak K, Harding S, Clarke K, Wells D, Marston S. 2010. Investigation of a transgenic mouse model of familial dilated cardiomyopathy. Journal of molecular and cellular cardiology 49:380-389. [NCBI PubMed Entry]
6. Olive M, Goldfarb LG, Lee HS, Odgerel Z, Blokhin A, Gonzalez-Mera L, Moreno D, Laing NG, Sambuughin N. 2010. Nemaline myopathy type 6: Clinical and myopathological features. Muscle & Nerve 42:901-907. [NCBI PubMed Entry]
7. Munot P, Lashley D, Jungbluth H, Feng L, Pitt M, Robb SA, Palace J, Jayawant S, Kennet R, Beeson D, Cullup T, Abbs S, Laing N, Sewry C, Muntoni F. 2010. Congenital fibre type disproportion associated with mutations in the tropomyosin 3 (TPM3) gene mimicking congenital myasthenia. Neuromuscular disorders 20:796-800. [NCBI PubMed Entry]
8. Sambuughin N, Yau KS, Olive M, Duff RM, Bayarsaikhan M, Lu S, Gonzalez-Mera L, Sivadorai P, Nowak KJ, Ravenscroft G, Mastaglia FL, North KN, Ilkovski B, Kremer H, Lammens M, van Engelen BG, Fabian V, Lamont P, Davis MR, Laing NG, Goldfarb LG. 2010. Dominant Mutations in KBTBD13, a Member of the BTB/Kelch Family, Cause Nemaline Myopathy with Cores. American journal of human genetics 87(6):842-7. [NCBI PubMed Entry]

Book Chapters

1. Wallgren-Pettersson C, Laing NG. 2010. Congenital myopathies. In: Karpati G, Hilton-Jones D, Bushby K, Griggs RC (eds) Disorders of Voluntary Muscle, 8th Edition. Cambridge University Press, Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, Sao Paulo, Delhi, Dubai, Tokyo. pp 282-298. [Cambridge Catalogue]

2011 Publications

1. Ravenscroft G, Wilmshurst JM, Pillay K, Sivadorai P, Wallefeld W, Nowak KJ, Laing NG. 2011. A novel ACTA1 mutation resulting in a severe congenital myopathy with nemaline bodies, intranuclear rods and type I fibre predominance. Neuromuscular Disorders 21(1):31-36. [NCBI PubMed Entry]
2. Ravenscroft G, Jackaman C, Bringans S, Papadimitriou JM, Griffiths LM, McNamara E, Bakker AJ, Davies KE, Laing NG, Nowak KJ. 2011. Mouse models of dominant ACTA1 disease recapitulate human disease and provide insight into therapies. Brain 134(Pt 4):1101-15. [NCBI PubMed Entry]
3. Saito Y, Komaki H, Hattori A, Takeuchi F, Sasaki M, Kawabata K, Mitsuhashi S, Tominaga K, Hayashi YK, Nowak KJ, Laing NG, Nonaka I, Nishino I. 2011. Extramuscular manifestations in children with severe congenital myopathy due to ACTA1 gene mutations. Neuromuscular Disorders 21:489-93. [NCBI PubMed Entry]
4. Duff RM, Tay V, Hackman P, Ravenscroft G, McLean C, Kennedy P, Steinbach A, Schoffler W, van der Ven PF, Furst DO, Song J, Djinovic-Carugo K, Penttila S, Raheem O, Reardon K, Malandrini A, Gambelli S, Villanova M, Nowak KJ, Williams DR, Landers JE, Brown RH Jr, Udd B, Laing NG. 2011. Mutations in the N-terminal Actin-Binding Domain of Filamin C Cause a Distal Myopathy. American Journal of Human Genetics 88(6):729-40. [NCBI PubMed Entry]
5. Lamont P, Wallefeld W, Davis M, Udd B, Laing N. 2011. Clinical utility gene card for: Laing distal myopathy. European Journal of Human Genetics 19(3). [NCBI PubMed Entry]
6. Scott AP, Laing NG, Mastaglia F, Needham M, Walter MC, Dalakas MC, Allcock RJ. 2011. Recombination mapping of the susceptibility region for sporadic inclusion body myositis within the major histocompatibility complex. Journal of Neuroimmunology 235(1-2):77-83. [NCBI PubMed Entry]
7. Song W, Dyer E, Stuckey DJ, Copeland O, Leung MC, Bayliss C, Messer A, Wilkinson R, Tremoleda JL, Schneider MD, Harding SE, Redwood CS, Clarke K, Nowak K, Monserrat L, Wells D, Marston SB. 2011. Molecular Mechanism of the E99K Mutation in Cardiac Actin (ACTC Gene) That Causes Apical Hypertrophy in Man and Mouse. Journal of Biological Chemistry 286(31):27582-93. [NCBI PubMed Entry]
8. Laing NG, Davis MR, Bayley K, Fletcher S, Wilton SD. 2011. Molecular diagnosis of duchenne muscular dystrophy: past, present and future in relation to implementing therapies. The Clinical Biochemist 32(3):129-34. [NCBI PubMed Entry]
9. Ravenscroft G, Sollis E, Charles AK, North KN, Baynam G, Laing NG. 2011. Fetal akinesia: review of the genetics of the neuromuscular causes. Journal of Medical Genetics 48(12):793-801. [NCBI PubMed Entry]
10. Ravenscroft G, Jackaman C, Sewry CA, McNamara E, Squire SE, Potter AC, Papadimitriou J, Griffiths LM, Bakker AJ, Davies KE, Laing NG, Nowak KJ. 2011. Actin nemaline myopathy mouse reproduces disease, suggests other actin disease phenotypes and provides cautionary note on muscle transgene expression. PloS One 6(12):e28699. [NCBI PubMed Entry]
11. Wallgren-Pettersson C, Sewry CA, Nowak KJ, Laing NG. 2011. Nemaline myopathies. Seminars in Pediatric Neurology 18(4):230-8. [NCBI PubMed Entry]

2012 Publications

1. Marttila M, Lemola E, Wallefeld W, Memo M, Donner K, Laing NG, Marston S, Gronholm M, Wallgren-Pettersson C. 2012. Abnormal actin binding of aberrant beta-tropomyosins is a molecular cause of muscle weakness in TPM2-related nemaline and cap myopathy. The Biochemical Journal 442(1):231-9. [NCBI PubMed Entry]