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  Street address:
Level 11, KGV Building
Missenden Road
CAMPERDOWN NSW 2050
 
Postal address:
Post Office Box M30
Missenden Road NSW 2050

Phone: (02) 9515-6111
Fax: (02) 9515-9610

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Neurobiology and Molecular Medicine

Our Research

Director: Professor Garth Nicholson
Principal Scientist: Associate Professor Marina Kennerson

The Northcott Neuroscience Laboratory, headed by Professor Garth Nicholson is internationally renowned in the field of molecular genetics of human hereditary neuropathies and motor neurone disorders. Together with Associate Professor Kennerson, the laboratory has made important contributions to the discovery of gene mutations causing neurodegeneration of peripheral nerve and motor neurons. The discovery of mutant genes in our families has uncovered new mechanisms causing disease. We are setting up ways to screen compounds for possible treatments. In hereditary sensory neuropathy we have commenced a pilot treatment trial.

Our laboratory is truly translational and focuses on determining the underlying causes of neurodegenerative disease firstly to develop diagnostic tools and eventually to develop effective treatment therapies.

Gene Discovery Program for Inherited Peripheral Neuropathies M Kennerson, M Brewer, A Cutrupi, A Drew, M Ellis, A Grant, A Kidambi, C Ly, G. Nicholson

Charcot-Marie-Tooth (CMT) disease CMT is a degenerative disorder of the peripheral nerve affecting both sensory and motor nerves. Individuals who suffer from this disorder experience distal muscle weakness of legs and arms, foot deformities and sensory loss. Motor and sensory neurons are unique cells with long axons (up to 1 metre) that require continuous maintenance from the cell body to the nerve endings. The breakdown of this maintenance leads to the 'dying back' of the nerve ends (axonal degeneration). Our research aim is to identify the biological pathways leading to axonal degeneration with the ultimate goal of developing treatments. To do this we identify the faulty gene in families with CMT disease.

Identifying genes for CMT disease has entered an exciting era in which availability of next generation sequencing (NGS) is expediting the gene discovery process. Central to our research has been the analysis of the largest CMT cohort in an Australian study using whole exoming sequencing. Our 'exomes' provide sequence information on all the known genes in our DNA. Over 300 patient exomes have been analysed for the 80 genes known to cause CMT in the one test. Through our research this method of gene testing has now been developed for a clinical setting and is offered as a CMT genetic test in our diagnostic laboratory which is a national reference centre for these disorders.

This year we provided definitive linkage data mapping an axonal form of CMT on chromosome 22 in which the causative MORC2 gene localises. In collaboration with colleagues at the University of Malaya we have used a combination of linkage and whole exome sequencing to map a new locus chromosome 14 and identify a causative gene for recessive CMT.

We have used whole genome sequencing which covers gene and non-gene DNA sequence. We have shown for the first time unique disease causing DNA re-arrangements in a family with X-lined CMT (CMTX3) and a family with hereditary motor neuropathy on chromosome 7 (DHMN1). Our discoveries have highlighted the importance of looking for DNA re-arrangements (structural variation) in families where the coding exons of genes have been eliminated.

Worm models for Inherited Peripheral Neuropathies M. Brewer, A. Siddell, G. Nicholson, M. Kennerson

This year we have introduced worm technology into the laboratory as a possible fast track screen for drug therapies for degenerative disorders of nerve. Caenorhabditis elegans (C. elegans) is a small (about 1 mm in length), transparent nematode with a short life cycle and a well characterised nervous system - making them ideal for studying axonal degeneration caused by genetic mutations found in patients with inherited peripheral neuropathy (IPN).

Candidate gene mutations will be overexpressed in the worm's GABA-motor neurons - which innervate the muscles that control worm locomotion. Gene variants that are pathogenic are expected to cause axonal degeneration as evidenced by abnormal locomotive behaviour and disrupted axon structure (observed visually by the endogenous expression of green fluorescent protein in the GABAergic neurons). This project complements our current gene discovery program by providing additional in vivo evidence as to whether a candidate gene mutation is the cause of inherited peripheral neuropathy in our patients. Models established in this project will be used for downstream functional studies and therapeutic drug screens.

Cell models of Inherited Peripheral Neuropathies G Perez-Siles, M. Ellis, A. Grant, A. Kidambi, C. Ly, A.Siddell, G. Nicholson, M. Kennerson

Our group has a cell biology program for the study of mutations causing inherited peripheral neuropathies. Understanding the normal function and the consequences of the mutations in neuronal cell lines, will further our understanding of the mechanisms causing degenerative nerve disease.

Two of the main projects currently developed in our lab involve the study of PDK3 and ATP7A mutations, previously identified by our group as causative disease mutations of two forms of X-linked distal hereditary motor neuropathy.

Using patient derived cells with the PDK3 gene mutation we have recently identified a highly potential 'drugable' target for therapeutic intervention. We have also successfully developed a knock-in mouse model that expresses a human mutation in the copper transporter ATP7A. This model faithfully recapitulates the defective molecular events observed in the human patient fibroblasts. We believe this model will facilitate identification and testing of therapeutic targets to develop effective copper based therapies for the disease.

Key Achievements

  • We have shown the importance of structural variation (SV) as a disease causing mechanism for a form of X-linked CMT (CMTX3). A 78-kb region of chromosome 8 has been inserted into the CMTX3 disease region and causes a change in gene dosage. The study of SV is an important initiative for our research to determine the contribution of pathogenic DNA re-arrangements as a cause of CMT.
  • We have demonstrated important molecular pathogenic changes in a mouse model for X-linked distal motor neuropathy. The mutated Atp7a copper transporter expressed in the mouse model shows trafficking defects and reduced protein mutant protein. This model will be a key resource to develop copper based therapies to prevent motor neuron degeneration.
  • This year we commenced a pilot trial in hereditary sensory neuropathy type 1 (HSN1) which is a motor and sensory neuropathy (a form of CMT). This disease is caused by a mutation in a gene (serine palmitoyl transferase) discovered by our group. The gene mutation results in production of a neurotoxic sphingolipid. The toxin be reduced by a dietary supplement serine. The pilot trial is developing measures to assess the treatment.
  • A/Prof Marina Kennerson was invited to teach a Gene Mapping Linkage Course for researchers and postgraduate students at the University of Malaya. She was also an invited lecturer for fourth year Biomedical Science students at University of Malaya.
  • A/Prof Marina Kennerson was an invited abstract reviewer and session chairperson for the 65th American Society of Human Genetics, Baltimore MD, USA.
  • A/Prof Kennerson was an invited session chairperson for the Peripheral Nerve Society Biennial Meeting Quebec City, Canada.
  • The group has been part of an initiative to bring together researchers in neuropathy across Sydney and participated in the inaugural Sydney Neuropathy Research Group (SyNRG) which is part of the Neuroscience Network at Sydney University. Our group contributes genomics/bioinformatics expertise and excellence in gene discovery skills.
  • Professor Nicholson is on the advisory board of the Inherited Neuropathy Consortium of the USA and is medical advisor to the CMT Association of Australia and is the patron of the MJD Foundation of Australia.

Awards/Medals

  • Peripheral Nerve Society Meeting Travel Award - awarded to Dr Megan Brewer and Dr Gonzalo Perez-Siles.
  • Sydney Medical School, University of Sydney ECR Travel Grant - Dr Megan Brewer.
  • Concord Repatriation General Hospital Travel Scholarship - Dr Megan Brewer.
  • Third Place for Concord Clinical Week 3 Minute Thesis Challenge - Dr Megan Brewer.
  • Short-listed for the Concord Hospital Early Career Research Award - Dr Megan Brewer.
  • Sydney Neuropathy Research Group (SyNRG) ECR Award - Dr Gonzalo Perez-Siles.

Research Staff

  • A/Prof Marina Kennerson PhD - Principal Research Fellow/Team Leader
  • A/Prof Stephen Reddel MBBS, PhD - Neurologist
  • Dr Angela Laird PhD - Postdoctoral Fellow
  • Dr Megan Brewer PhD - Postdoctoral Fellow
  • Dr Gonzalo Perez-Siles PhD - Postdoctoral Fellow
  • Dr Alexander Drew PhD - Postdoctoral Fellow
  • Carolyn Ly BMedSc (Hons) - Research Assistant
  • Aditi Kidambi BSc (Hons) - Research Assistant
  • Melina Ellis BSc (Hons) - Research Assistant
  • Kristy Yuan BSc (Hons) - Research Assistant
  • Jody O'Connor BHSc, MPH - Research Assistant
  • Adrienne Grant BA - Technical Officer

Higher Degree Students:

PhD: 

  • Ms Shelisa Tey

Masters:

  • Ms Anna Siddell


Publications and Presentations

Publication Details:
  1. Coutelier M, Goizet C, Durr A, Habarou F, Morais S, Dionne-Laporte A, Tao F, Konop J, Stoll M, Charles P, Jacoupy M, Matusiak R, Alonso I, Tallaksen C, Mairey M, Kennerson M, Gaussen M, Schule R, Janin M, Morice-Picard F, Durand CM, Depienne C, Calvas P, Coutinho P, Saudubray JM, Rouleau G, Brice A, Nicholson G, Darios F, Loureiro JL, Zuchner S, Ottolenghi C, Mochel F, Stevanin G. Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia. Brain : a journal of neurology. 2015;138:2191-2205.
  2. Drew AP, Zhu D, Kidambi A, Ly C, Tey S, Brewer MH, Ahmad-Annuar A, Nicholson GA, Kennerson ML. Improved inherited peripheral neuropathy genetic diagnosis by whole-exome sequencing. Molecular genetics & genomic medicine. 2015;3:143-154.
  3. Fifita JA, Williams KL, McCann EP, O'Brien A, Bauer DC, Nicholson GA, Blair IP. Mutation analysis of MATR3 in Australian familial amyotrophic lateral sclerosis. Neurobiology of aging. 2015;36:1602 e1601-1602.
  4. Geevasinga N, Menon P, Howells J, Nicholson GA, Kiernan MC, Vucic S. Axonal ion channel dysfunction in c9orf72 familial amyotrophic lateral sclerosis. JAMA neurology. 2015;72:49-57.
  5. Geevasinga N, Menon P, Nicholson GA, Ng K, Howells J, Kril JJ, Yiannikas C, Kiernan MC, Vucic S. Cortical Function in Asymptomatic Carriers and Patients With C9orf72 Amyotrophic Lateral Sclerosis. JAMA neurology. 2015;72:1268-1274.
  6. Peeters K, Bervoets S, Chamova T, Litvinenko I, De Vriendt E, Bichev S, Kancheva D, Mitev V, Kennerson M, Timmerman V, De Jonghe P, Tournev I, MacMillan J, Jordanova A. Novel mutations in the DYNC1H1 tail domain refine the genetic and clinical spectrum of dyneinopathies. Human mutation. 2015;36:287-291.
  7. Strickland AV, Schabhuttl M, Offenbacher H, Synofzik M, Hauser NS, Brunner-Krainz M, Gruber-Sedlmayr U, Moore SA, Windhager R, Bender B, Harms M, Klebe S, Young P, Kennerson M, Garcia AS, Gonzalez MA, Zuchner S, Schule R, Shy ME, Auer-Grumbach M. Mutation screen reveals novel variants and expands the phenotypes associated with DYNC1H1. Journal of neurology. 2015;262:2124-2134.
  8. Williams KL, McCann EP, Fifita JA, Zhang K, Duncan EL, Leo PJ, Marshall M, Rowe DB, Nicholson GA, Blair IP. Novel TBK1 truncating mutation in a familial amyotrophic lateral sclerosis patient of Chinese origin. Neurobiology of aging. 2015;36:3334 e3331-3335.
  9. Yang S, Zhang KY, Kariawasam R, Bax M, Fifita JA, Ooi L, Yerbury JJ, Nicholson GA, Blair IP. Evaluation of Skin Fibroblasts from Amyotrophic Lateral Sclerosis Patients for the Rapid Study of Pathological Features. Neurotoxicity research. 2015;28:138-146.

Presentations:

Oral Presentations:

  1. Kennerson ML Inherited peripheral neuropathy genomics gene discovery program at Concord Hospital. Sydney Neuropathy Research Group Symposium: Children's Hospital Westmead, February 2015.
  2. Brewer MH, Chaudhry R, Qi J, Drew A, Kidambi A, Menezes M, Zuchner S, Nicholson G and Kennerson M X-linked Charcot-Marie-Tooth neuropathy (CMTX3) is caused by an insertion translocation into a mutation hotspot palindrome at Xq27.1. Australian Society of Medical Research (ASMR) NSW Scientific Meeting, Sydney, Australia, June 2015.
  3. Kennerson ML*, Albulym OM*, Drew AP, Siddell A, Harms M, Auer-Grumbach M, Pestronk A, Connolly A, Baloh RH, Reddell R, Zuchner S, Nicholson GA A combination of linkage analysis and whole exome sequencing identifies a new cause of Charcot-Marie-Tooth neuropathy (CMT2) with pyramidal signs. Gene Mappers Meeting: Perth, Western Australia, Australia, November 2015. * equal first authors.

Poster Presentations:

  1. Tey S, Shahrizaila N, Goh KJ, Drew AP, Nicholson G, Kennerson ML*, Ahmad-Annuar A Finding the causative gene mutation in a consanguineous family with Charcot-Marie-Tooth (CMT) disease. Human Genome Meeting 2015 (HGM2015), Kuala Lumpur, Malaysia, March 2015. * Equal senior author.
  2. Ahmad-Annuar A, Tey S, Shahrizaila N, Goh KJ, Ch'ng G-S, Nicholson GA and Kennerson ML Identification of causal genes through whole exome sequencing in a Malaysian cohort of Charcot-Marie-Tooth patients. Human Genome Meeting 2015 (HGM2015), Kuala Lumpur, Malaysia, March 2015.
  3. Cutrupi A, Drew AP, Brewer MH, Nicholson GA and Kennerson ML Extensive molecular analysis of a motor neuropathy family allows assessment of the sensitivity and annotation accuracy of whole genome sequencing. Australian Society of Medical Research (ASMR) NSW Scientific Meeting, Sydney, Australia, June 2015.
  4. Siddell A, Albulym O, Perez-Siles G, Brewer M, Nicholson G, Kennerson M Unveiling the pathogenic molecular mechanisms of MORC2 mutations causing Charcot-Marie-Tooth disease. Australian Society of Medical Research (ASMR) NSW Scientific Meeting, Sydney, Australia, June 2015.
  5. Kennerson ML, Brewer MH, KOnchanski A, Kidambi A, Drew AP, Perez-Siles G, Grant A, Kosinska J, Kabzinska D, Ploski R, Hausmanowa-Petrusewicz and Nicholson GA Progress in identifying the gene for CMTX3. Peripheral Nerve Society Biennial Meeting 2015, Quebec City, Quebec, Canada, June 2015.
  6. Brewer MH, Chaudhry R, Qi J, Drew A, Kidambi A, Menezes M, Zuchner S, Nicholson G, Kennerson M X-linked Charcot-Marie-Tooth neuropathy (CMTX3) is caused by an insertion translocation into a mutation hotspot palindrome at Xq27.1. Peripheral Nerve Society Biennial Meeting 2015, Quebec City, Quebec, Canada, June 2015.
  7. Perez-Siles G, Yiu E, Ryan MM, Chuang D, Tso S, Grant A, Nicholson GA, Kennerson ML Understanding the pathogenic mechanisms underlying X-linked Charcot-Marie-Tooth neuropathy (CMTX6) caused by the R158H PDK3 mutation. Peripheral Nerve Society Biennial Meeting 2015, Quebec City, Quebec, Canada, June 2015.
  8. Nicholson GA, Drew AP, Ellis M, Brewer MH and Kennerson ML Missing heritability is common in inherited peripheral neuropathy families without known mutations and may be caused by structural variations in non coding DNA. A novel mechanism? Peripheral Nerve Society Biennial Meeting 2015, Quebec City, Quebec, Canada, June 2015.
  9. Ahmad-Annuar A, Tey S, Shahrizaila T, Goh KJ, Drew AP, Brewer M, Kidambi A, Nicholson G and Kennerson ML Whole exome sequencing of a Malaysian family reveals a novel candidate gene for autosomal recessive CMT. Peripheral Nerve Society Biennial Meeting 2015, Quebec City, Quebec, Canada, June 2015.
  10. Kennerson ML*, Albulym OM*, Drew AP, Harms M, Auer-Grumbach M, Pestronk A, Connolly A, Baloh RH, Reddell R, Zuchner S, Nicholson GA Linkage mapping and exome sequencing identifies a novel genetic cause of Charcot-Marie-Tooth neuropathy with pyramidal signs. 64th American Society of Human Genetics, Baltimore, Marylands, USA, October 2015. * equal first authors
  11. Drew AP, Brewer MH, KOnchanski A, Kidambi A, Perez-Siles G, Grant A, Kosinska J, Kabzinska D, Ploski R, Hausmanowa-Petrusewicz, Nicholson GA and Kennerson ML Whole Genome Sequencing Identifies Structural Variation and Non-Coding Variants in the Region Overlapping the CMTX3 and CMTX4 Loci. AGTA Conference: Hunter Valley NSW, Australia, October 2015.
  12. Brewer MH, Chaudhry R, Qi J, Drew A, Kidambi A, Menezes M, Zuchner S, Nicholson G, Kennerson M, A 78 kb translocation insertion into a mutation hot spot palindrome sequence at Xq27.1 causesX-linked Charcot-Marie-Tooth neuropathy (CMTX3). Gene Mappers Meeting: Perth, Western Australia, Australia, November 2015.
  13. Drew AP, Brewer MH, Konchanski A, Kidambi A, Perez-Siles G, Grant A, Kosinska J, Kabzinska D, Ploski R, Hausmanowa-Petrusewicz, Nicholson GA and Kennerson ML Mutation screening in a family with axonal CMT localised to chromosome Xq25-q27.2. Gene Mappers Meeting: Perth, Western Australia, Australia, November 2015.
  14. Siddell A, Albulym O, Perez-Siles G, Brewer M, Nicholson G and Kennerson ML Epigenetics: a potential new pathomechanism underlying Charcot-Marie-Tooth neuropathy. Epigenetics Australian Scientific Conference, Hobart, Tasmania, Australia, November 2015.

Research Grants

GRANTING BODY AWARDEES PROJECT TITLE Total $$ Years
NHMRC Kennerson and Nicholson Gene identification for inherited peripheral neuropathies by applying next generation sequencing.  $585,000 2013-2015
Sydney Medical School Tony Basten Fellowship Scheme Brewer Establishing a model organism-based pipeline using C. elegans to identify novel gene mutations causing axonal degeneration  $   50,000 2015
Sydney Research Annual Health Research Infrastructure Award  Brewer Identifying novel gene mutations that cause axonal degeneration of the peripheral nerves using a C. elegans (worm) model  $   10,000 2015
Sydney Neuroscience Network Drew Completing the pathogenic landscape of inherited peripheral neuropathies by assessing structural variation using whole genome sequencing.  $   10,000 2015

Contact details for department

Head of Department: Professor Garth Nicholson

Department/Unit: Neurobiology and Molecular Medicine
Address:
Other
Clinical Sciences Building
Concord NSW 2139
Telephone: (02) 9767 6796
Facsimile: (02) 9767 6991
Web: http://www.slhd.nsw.gov.au/research/
Email: marinak@anzac.edu.au