WIMM PI
Curriculum Vitae
Personal Data
Name
Nationality
Email
Zameel Cader
UK
zameel.cader@ndcn.ox.ac.uk
Present Position
2007-present
2013-present
2012-present
2013-present
2014-present
Honorary Consultant in Neurology (Oxford University Hospitals Trust)
Director of the Oxford Headache Centre (Oxford University Hospitals Trust)
Director of IMI StemBANCC (University of Oxford)
Principal Investigator WIMM
Associate Professor in Clinical Neurosciences
Previous Positions
2012-2014
Senior Clinician Scientist
Department of Clinical Neurology
West Wing, John Radcliffe Hospital
Off Headley Way, Oxford OX3 9DU
2007-2011
MRC Clinician Scientist
Functional Genomics Unit, Oxford Centre for Gene Function
Department of Physiology, Anatomy and Genetics
South Parks Road, Oxford OX1 3QX
2003-2007
Specialist Registrar (Neurology)
Department of Clinical Neurology
West Wing, John Radcliffe Hospital
Off Headley Way, Oxford OX3 9DU
2000-2003
MRC Clinical Research Training Fellow
Wellcome Trust Centre for Human Genetics
Roosevelt Drive, Oxford, OX3 7BN
1998-2000
Senior House Officer (Medicine)
Oxford Radcliffe Hospitals NHS Trust, Oxford
1997-1998
House Officer
University of Birmingham Hospitals NHS Trust, Birmingham
Research Achievements
Over the past 6 years, I have been developing an independent research career and
establishing my research group. We aim to understand how rare and common gene variants
interact functionally at a cellular and systems level to cause neurological disorders. Our
disease areas of interest are migraine and neurodegeneration. My group now uses our
unique cell culture and animal models to identify novel drug targets. Through collaboration
with MRCT and industry to screen compound libraries against these targets, we have
identified hit compounds which we will continue to develop towards clinical application. I
recently successfully led a large consortium bid (25 academic partners, 11 pharma partners)
to develop human induced pluripotent stem cells (hiPSC) as a platform for drug discovery.
The major objectives of StemBANCC are generate a well curated large bio-repository of
hiPSC from a range diseases and to derive assay platforms for phenotypic drug screens.
My interest in the genetics of migraine began during my graduate studies and this work led to
the first identified gene associated with a common form of migraine. This was published in
Nature Medicine in September 2010 with significant worldwide media interest. We are now
building on this discovery using next-generation sequencing to identify other causative
interacting genes, developing in vitro and in vivo models, including using patient derived
stem cell models. We have now found the first example of oligogenic inheritance in migraine
with cell-autonomous and systems-level interactions between migraine causative genes.
An important and difficult question in neurology, is how mutations in essential and ubiquitous
proteins can lead to selective toxicity of neurons. Answering this question, would provide
significant insights in many disorders. We have been examining a rare form of axonal
neuropathy caused by dominant mutations in the gene, GARS encoding the ubiquitous
house-keeping enzyme Glycyl-tRNA synthetase. We have found disease and neuronal
specificity arise from a remarkable mechanism: disease mutations confer non-canonical
functions, whereby this cytoplasmic enzyme is secreted by muscle and interacts with axonal
guidance receptors on motor neurons, leading to non-cell autonomous toxicity.
What are the Future Aims of Your Current Group?
The future aims of our group are to comprehensively address the molecular and cellular
mechanisms of migraine. This will require new genomic approaches integrated with cellular
and animal model phenotyping. Specifically we will use gene network and pathway analyses
from hits identified in genome wide association and exome sequencing studies to generate
hypotheses for disease mechanism. We can then undertake deep phenotyping of stem cell
derived neurons from patients with migraine including intrinsic neurophysiological properties,
synaptic function, ionic homeostasis and kinase cascades. Through exposure to known
migraine inducers and migraine therapeutics followed by molecular profiling including single
cell omics, we aim to identify key molecular players to then develop new migraine therapies.
We will also use cell culture systems and animal models to explore how systems level
pathologies may emerge. For example, migraine candidate genes may exert effects on
distinct brain regions. Through generating compound mouse models and using ex-vivo brain
slice electrophysiology and in vivo electrophysiology, we can gain a better understanding of
how these genes affect particular brain regions and how such regions interact to produce
emergent phenotypes. We will continue to work with groups such as MRCT to translate these
findings into drug screens and drug development pipelines.
How do These Aims Contribute to the Understanding and/or Management of Human
Disease
Migraine is a disorder affecting 1 in 10 people worldwide at any one time and 1 in 3 people
during their lifetime. The World Health Organization ranks it as one of the leading causes of
disability. However research and healthcare provision are hugely inadequate for such an
important disorder. Our work will embody the philosophy of the WIMM, developing
hypotheses originating from human studies and observations to then test with innovative
research methods. We have now started to move beyond the single rare variant gene model
or indeed common variant hypothesis for migraine since these approaches are reaching their
limits. Instead we are developing new paradigms and new techniques including cellular
association studies to identify the molecular determinants of disease. This will require
collaborations with key researchers at the forefront of medical research, including several
within the WIMM.
Lay Summary of Research
Headaches are common, costly and debilitating conditions. Their impact on the individual
and to society is often hugely underestimated. Migraine, an important type of headache,
affects one in three people over a lifetime and the World Health Organisation now ranks
migraine as a leading cause of disability worldwide. For some patients migraine headaches
can blight lives for years. Our group is aiming to find out why some people suffer with
migraine. We know a major reason lies in our genes and we have found the first gene
underlying typical migraine. We identified in a large family with migraine, a defect in the gene
KCNK18, which encodes an ion channel called TRESK. TRESK is present in parts of the
brain important for the development of migraine and our studies have shown that mutations
in TRESK can make nerves more excitable. However there are many other genes that are
also likely to predispose to migraine but they are challenging to uncover. We are using the
latest technologies to reveal new migraine genes and trying to understand how different
genes can interact with each other to increase migraine susceptibility.
This includes the use of stem cell models of migraine. When we develop from an embryo
into our adult forms, all the different specialized cells of our body arise from a type of cell
called a stem cell. The two key properties of stem cells are their ability to renew themselves
and to become any cell type in the body (a property called pluripotency). It is now possible to
turn the clock back and transform an adult cell such as a skin or blood cell from a patient
back into a stem cell. These induced pluripotent stem cells contain all the DNA and genes of
the patient. We are using stem cells from patients with migraine, that we then turn into nerve
cells. For the first time, we now have a way to directly assess how a migraine patient’s
nerves differ from people who don’t get migraine and link this with the genetic make-up of
the patient.
All Publications Over the Past 5 Years
Sleigh JN, Burgess RW, Gillingwater TH, Cader MZ. Morphological analysis of
neuromuscular junction development and degeneration in rodent lumbrical muscles.
J Neurosci Methods. 2014 Apr 30;227:159-65.
Wright PD, Weir G, Cartland J, Tickle D, Kettleborough C, Cader MZ, Jerman J.
Cloxyquin (5-chloroquinolin-8-ol) is an activator of the two-pore domain
potassium channel TRESK. Biochem Biophys Res Commun. 2013 Nov 15;441(2):463-8.
Sleigh JN, Grice SJ, Burgess RW, Talbot K, Cader MZ. Neuromuscular junction
maturation defects precede impaired lower motor neuron connectivity in
Charcot-Marie-Tooth type 2D mice. Hum Mol Genet. 2014 May 15;23(10):2639-50.
Cader MZ. The molecular pathogenesis of migraine: new developments and opportunities.
Hum Mol Genet. 2013 Aug 14.
Németh AH, Kwasniewska A, Lise S, Schnekenberg RP, Becker E, Bera K, Shanks ME,
Gregory L, Buck D, Cader MZ, Talbot K, de Silva R, Fletcher N, Hastings R, Jayawant S,
Morrison PJ, Worth P, Taylor M, Tolmie J, O’Regan M, Fuller G, UK Ataxia Consortium,
Valentine P, Packham V, Evans J, Seller A, Ragoussis J. Next Generation Sequencing for
Molecular Diagnosis of Neurological Disorders using Ataxias as a Model. Brain (accepted)
Janssen BJC, Maliauskas T, Weir GA, Cader MZ, Siebold C, Jones EY. Neuropilins lock
secreted semaphorins onto plexins in a ternary signalling complex. Nature Structural and
Molecular Biology 2012 Dec;19(12):1293-9
Lise S, Clarkson Y, Perkins E, Kwasniewska A, Sadighi Akha E, Parolin Schnekenberg R,
Suminaite D, Hope J, Baker I, Gregory L, Green A, Allan C, Lamble S, Jayawant S,
Quaghebeur G, Cader MZ, Hughes S, Armstrong RJ, Kanapin A, Rimmer A, Lunter G,
Mathieson I, Cazier JB, Buck D, Taylor JC, Bentley D, McVean G, Donnelly P, Knight SJ,
Jackson M, Ragoussis J, Németh AH. Recessive Mutations in SPTBN2 Implicate β-III
Spectrin in Both Cognitive and Motor Development. PLoS Genet. 2012 Dec;8(12)
Dyment AD, Cader MZ et al. Exome sequencing identifies a novel, multiple sclerosis
susceptibility variant in the TYK2 gene. Neurology. Jul 31;79(5):406-11
Andres-Enguix I, Shang L, Stansfeld PJ, Morahan JM, Sansom MS, Lafrenière RG, Roy B,
Griffiths LR, Rouleau GA, Ebers GC, Cader ZM*, Tucker SJ*. Functional analysis of
missense variants in the TRESK (KCNK18) K channel. Sci Rep. 2012;2:237. *joint
corresponding author
Ramagopalan SV, Dyment DA, Cader MZ, Morrison KM, Disanto G, Morahan JM, BerlangaTaylor AJ, Handel A, De Luca GC, Sadovnick AD, Lepage P, Montpetit A, Ebers GC. Rare
variants in the CYP27B1 gene are associated with multiple sclerosis. Ann Neurol. 2011
Dec;70(6):881-6.
Weir GA, Cader MZ. New directions in migraine. BMC Med. 2011 Oct 25;9:116.
Lafrenière RG*, Cader MZ*, Poulin JF, Andres-Enguix I, Simoneau M, Gupta N, Boisvert K,
Lafrenière F, McLaughlan S, Dubé MP, Marcinkiewicz MM,Ramagopalan S, Ansorge O,
Brais1 B, Sequeiros J, Pereira-Monteiro JM, Griffiths LR, Tucker SJ, Ebers G & Rouleau
GA. A dominant-negative mutation in the TRESK potassium channel is linked to familial
migraine with aura. Nature Medicine 2010 Sept. *Joint first authors
Achilli F, Bros-Facer V, Williams HP, Banks GT, Alqatari M, Chia R, Tucci V, Groves M,
Nickols CD, Seburn KL, Kendall R, Cader MZ, Talbot K, van Minnen J, Burgess RW,
Brandner S, Martin JE, Koltzenburg M, Greensmith L, Nolan PM, Fisher EM. An ENUinduced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and
motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy.
Dis Model Mech. 2009 May 26
Gayán J, Brocklebank D, Andresen JM, Alkorta-Aranburu G; US-Venezuela Collaborative
Research Group, Zameel Cader M, Roberts SA, Cherny SS, Wexler NS, Cardon LR,
Housman DE. Genomewide linkage scan reveals novel loci modifying age of onset of
Huntington's disease in the Venezuelan HD kindreds. Genet Epidemiol.
2008
Jul;32(5):445-53.
Dyment DA, Cader MZ, Datta A, Broxholme SJ, Cherny SS, Willer CJ, Ramagopalan S,
Herrera BM, Orton S, Chao M, Sadovnick AD, Hader M, Hader W, Ebers GC. A first stage
genome-wide screen for regions shared identical-by-descent in Hutterite families with
multiple sclerosis. Am J Med Genet B Neuropsychiatr Genet. 2008 Jun 5;147B(4):467-72.
Key Publications Throughout your Career
Sleigh JN, Grice SJ, Burgess RW, Talbot K, Cader MZ. Neuromuscular junction
maturation defects precede impaired lower motor neuron connectivity in
Charcot-Marie-Tooth type 2D mice. Hum Mol Genet. 2014 May 15;23(10):2639-50.
Lafrenière RG*, Cader MZ*, Poulin JF, Andres-Enguix I, Simoneau M, Gupta N, Boisvert K,
Lafrenière F, McLaughlan S, Dubé MP, Marcinkiewicz MM,Ramagopalan S, Ansorge O,
Brais1 B, Sequeiros J, Pereira-Monteiro JM, Griffiths LR, Tucker SJ, Ebers G & Rouleau
GA. A dominant-negative mutation in the TRESK potassium channel is linked to familial
migraine with aura. Nature Medicine 2010 Sept. *Joint first authors
Cader MZ, Noble-Topham SE, Dyment DA, Brown JD, Rice GPA, Ebers GC. Significant
linkage to migraine with aura on chromosome 11q24. Human Molecular Genetics 2003
OCT 12(19): 2511-17
Lincoln MR, Montpetit A, Cader MZ, Saarela J, Dyment DA, Tiislar M, Ferretti V, Tienari PJ,
Sadovnick AD, Peltonen L, Ebers GC, Hudson TJ. A predominant role for the HLA class II
region in the association of the MHC region with multiple sclerosis. Nature Genetics. 2005
Oct;37(10):1108-12.
Janssen BJC, Maliauskas T, Weir GA, Cader MZ, Siebold C, Jones EY. Neuropilins lock
secreted semaphorins onto plexins in a ternary signalling complex. Nature Structural and
Molecular Biology 2012 Dec;19(12):1293-9
Cader MZ, Ren J, James PA, Bird LE, Talbot K, Stammers DK. Crystal structure of human
wildtype and S581L-mutant glycyl-tRNA synthetase, an enzyme underlying distal spinal
muscular atrophy. FEBS Letters 2007 Jun 26;581(16):2959-64.
James PA, Cader MZ, Muntoni F, Childs A, Crow YJ, Talbot K. Severe Childhood SMA And
Axonal CMT Due To Anti-Codon Binding Domain Mutations In The GARS Gene. Neurology
2006 Nov 14;67(9):1710-2
Current Grant Support
IMI StemBANCC, 2012 – 2017
AFM Project Grant, 2013 – 2015
BRC Funding, 2012 - 2017
John Fell Fund Award, 2012 – 2014
Student support:
Greg Weir: Hertford College Scholarship
Charles Masaki; Rhodes Scholarship
Erfan Suliman: Clarendon Scholarship
Levan Chikobava: Erasmus Scholarship
€52m
€93, 000
£210, 000
£47,000