Dr Shireen Lamande

contact details

  Dr Shireen Lamandé
  Muscular Dystrophy
  Murdoch Childrens Research Institute
  Royal Children's Hospital
  Flemington Road
  Parkville Victoria 3052

  T +61 3 8341 6465
  F +61 3 9345 7997
  E shireen.lamande@mcri.edu.au

biography

• PhD, 1994, University of Melbourne; Molecular analysis of naturally occurring and engineered collagen mutations.
• Post-doctoral researcher, 1995-2003, University of Melbourne
• Group Leader, Murdoch Childrens Research Institute, 2004-
• Member of the Editorial Advisory Board for the Biochemical Journal 2006-
• National Health & Medical Research Council Senior Research Fellow, 2007-
• Immediate Past-President, Matrix Biology Society of Australia and New Zealand
• Vice-President, International Society of Matrix Biology 2011-

My research is focussed on the molecular genetics of inherited disorders of the musculoskeletal system.  My work has defined mutations leading to musculoskeletal disorders such as osteogenesis imperfecta ("brittle bone disease"), premature arthritis, and muscular dystrophies and is characterised by detailed biochemical studies that explore the effect of the mutations on protein structure and function and the organisation of the extracellular matrix of musculoskeletal tissues. 

In addition to defining genotype-phenotype relationships that pave the way for improved diagnosis and the development of rational therapeutic approaches, my work also contributes to understanding the complex multimeric assembly processes and interactions that underlie the formation of architecturally-precise and tissue-specific extracellular matrices that provide both a structural scaffolding and regulatory signals for growth and development. 

achievements

Awarded the 2006 Solander Fellowship by the University of Melbourne and Lund University for a short specialised electron microscopy project at Lund University. The Solander Program is an initiative to promote, widen and support scientific exchange between Universitas 21; Universities in Sweden, Australia and New Zealand.

research focus & interest

Our goal is to understand the causes of inherited musculoskeletal disease and identify pathogenic pathways, modifying genes and potential therapies.  Our research has three interrelated and overlapping streams.  The first two streams, collagen VI-related disorders and modifying genes and therapies, make up the muscular dystrophy program.  Mutations in the extracellular matrix protein collagen VI underlie two muscular dystrophies, Bethlem myopathy and Ullrich congenital muscular dystrophy (UCMD). 

We have studied ~100 patients, identified collagen VI mutations in more than 60 patients, and explored how the mutations affect collagen VI intracellular protein folding and assembly, and extracellular microfibril formation.  We are now focussing on two new research areas: using protein structural techniques to discriminate pathogenic changes from polymorphisms and; identifying new genes that underlie muscular dystrophy in the 30% of Bethlem and UCMD patients who do not have collagen VI mutations.  To date there is no effective therapy for muscular dystrophy.  It is likely that any eventual therapy will be multi-faceted, targeting multiple pathogenic pathways.  Our modifying genes and therapies research stream is identifying new therapeutic targets in muscular dystrophy using ENU mutagenesis to identify genetic modifiers of the dystrophic process, exploring nutraceutical therapies, and studying the role of fibrosis and extracellular matrix turnover in muscle pathology.

Our third research stream is a gene discovery program which is identifying new genes for skeletal disorders and studying disease mechanisms.  The major current project in this stream focuses on our exciting recent discovery that mutations in the ion channel, TRPV4, cause a novel form of premature hand arthritis.  We have also mapped the genes for three other inherited skeletal disorders and are using whole genome sequencing approaches to identify the disease genes and mutations.

publications

Lamandé, SR, Morgelin, M., Adams, NE, and Selan C (2006) The C5 domain of the collagen VI 3(VI) chain is critical for extracellular microfibril formation and is present in the extracellular matrix of cultured cells. Journal of Biological Chemistry.  281, 16607-16614

Baker, NL, Mörgelin, M, Pace, RA, Peat, RA, Adams, NE, Gardner, RJM, Rowland, LP, Miller, G, De Jonghe, P, Ceulemans, B, Hannibal, MC, Edwards, M, Thompson, EM, Jacobson, R, Quinlivan, RCM, Aftimos, S, Kornberg, AJ, North, KN, Bateman, JF and Lamandé, SR (2007) Molecular consequences of dominant Bethlem myopathy collagen VI mutations. Ann Neurol 62, 390-405

Sipila, L, Huotsalainen, H, Sormunen, R, Baker, NL, Lamandé, SR, Vapola, M, Wang, C, Sado, Y, Aszodi, A and Myllyla R (2007) Secretion and assembly of type IV and VI collagens depend on glycosylation of hydroxylysines.  J Biol Chem 282, 33381-33388

Peat, RA, Smith, JM, Compton, AG, Baker, NL, Pace RA, Burkin DJ, Kaufman SJ, Lamandé, SR and North, KN (2007) The diagnosis and etiology of congenital muscular dystrophy.  Neurology 71, 312-321

Tan, JT, Kremer, F, Freddi, S, Bell, KM, Baker, NL, Lamandé, SR and Bateman, JF (2008) Competency for nonsense-mediated reduction in collagen X mRNA is specified by the 3'UTR and corresponds to the position of mutations in Schmid metaphyseal chondrodysplasia.  Am J Hum Genet.  82, 786-93

Pace, RA, Peat, RA, Baker, NL, Zamurs, L, Mörgelin, M, Irving, M, Adams, NE, Bateman, JF, Mowat, D, Smith, NJC, Lamont, PJ, Moore, SA, Mathews, KD, North,KN, and Lamandé, SR (2008) Collagen VI glycine mutations: perturbed assembly and a spectrum of clinical severity.  Annals of Neurology. 64, 294-303

Bateman, JF, Boot-Handford, RP and Lamandé, SR. (2009) Genetic diseases of connective tissues: Cellular and extracellular effects of ECM mutations.  Nature Reviews Genetics. 10, 173-183

Allen, JM, Zamurs, L, Brachvogel, B, Schlotzer-Schrehardt, U, Hansen, U, Lamandé, SR, Fitzgerald, J, Rowley, L, Bateman, JF (2009) Mice lacking the extracellular matrix protein WARP develop normally but have compromised peripheral nerve structure and function.  J. Biol. Chem. 284, 12020-12030

Risteli, M, Ruotsalainen, H, Salo, AM, Sormunen, R, Sipila, L, Baker, NL, Lamandé, SR, Vimpari-Kauppinen, L, Myllyla, R (2009) Reduction of lysyl hydroxylase 3 causes deleterious changes in the deposition and organization of extracellular matrix. J Biol Chem 284, 28204-28211

Tooley, LD, Zamurs, LK, Beecher, N, Baker, NL, Peat, RA, Adams, NE, Bateman, JF, North, KN, Baldock, C, Lamandé, SR (2010) Collagen VI microfibril formation is abolished by an α2(VI) von Willebrand factor type A domain mutation in a patient with Ullrich congenital muscular dystrophy.  J Biol Chem 285, 33567-33576

Lamandé, SR, Yuan, Y, Gresshoff, IL, Rowley, L, Belluoccio, D, Kaluarachchi, K, Little, CB, Botzenhart, E, Zerres, K, Amor, DJ, Cole WG, Savarirayan, R, McIntyre, P, Bateman, JF (2011) Mutations in TRPV4 cause an inherited arthropathy of hands and feet.  Nature Genetics, published online 2 October 2011.