Professor Derek Blake

Professor of Neuroscience, Division of Psychological Medicine and Clinical Neurosciences

: blakedj@cardiff.ac.uk
: +44 (0)29 2068 8468
: 2.52, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ

: Media commentator
: Available for postgraduate supervision

My research is focussed on the molecular basis of a range of inherited disorders (eg. neurodevelopmental syndromes and muscular dystrophies) that affect the brain and striated muscle. I use a range of molecular biology techniques to determine the cellular function of proteins involved in the aforementioned disorders. I am particularly interested in the effects of mutations and polymorphisms on protein function since these studies can identify underlying pathologies and potential therapies. We also use functional genomics and proteomic techniques to study disease mechanisms in common, polygenic disorders including schizophrenia, Alzheimer's disease and Fuchs' endothelial corneal dystrophy (FECD).

1998

Loh, N. Y.et al. 1998. Genomic organization and refined mapping of the mouse beta-dystrobrevin gene. Mammalian Genome 9(11), pp. 857-862.
Loh, N. Y.et al. 1998. Genomic organization and refined mapping of the mouse β-dystrobrevin gene. Mammalian Genome 9(11), pp. 857-862. (10.1007/s003359900883)
Nawrotzki, R.et al. 1998. Characterisation of alpha-dystrobrevin in muscle. Journal of Cell Science 111(17), pp. 2595-2605.
Vater, R.et al. 1998. Utrophin mRNA expression in muscle is not restricted to the neuromuscular junction. Molecular and Cellular Neuroscience 10(5-6), pp. 229-242. (10.1006/mcne.1998.0661)
Blake, D. J.et al. 1998. beta-dystrobrevin, a member of the dystrophin-related protein family. Proceedings of the National Academy of Sciences of the United States of America 95(1), pp. 241-246. (10.1073/pnas.95.1.241)
Blake, D. J.et al. 1998. β-dystrobrevin, a member of the dystrophin-related protein family. Proceedings of the National Academy of Sciences of the United States of America 95(1), pp. 241-246.

1997

Blake, D. J.et al. 1997. The function dystrophin-related and -associated proteins in the brain. Journal of Neurochemistry 69(S), pp. S123-S123.
Blake, D. J.et al. 1997. A novel dystrophin-associated protein in brain. American Journal of Human Genetics 61(4), pp. A8-A8.
Loh, N. Y.et al. 1997. Beta-dystrobrevin; a new member of the dystrophin-related protein family. American Journal of Human Genetics 61(4), pp. A177-A177.
Metzinger, L.et al. 1997. Dystrobrevin deficiency at the sarcolemma of patients with muscular dystrophy. Human Molecular Genetics 6(7), pp. 1185-1191. (10.1093/hmg/6.7.1185)
Ponting, C. P.et al. 1997. PDZ domains: targeting signalling molecules to sub-membranous sites. Bioessays 19(6), pp. 469-479. (10.1002/bies.950190606)
Ambrose, H. J.et al. 1997. Genomic organization of the mouse dystrobrevin gene: comparative analysis with the dystrophin gene. Genomics 39(3), pp. 359-369. (10.1006/geno.1996.4515)

1996

Picketts, D. J.et al. 1996. ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome. Human Molecular Genetics 5(12), pp. 1899-1907. (10.1093/hmg/5.12.1899)
Morrison, K. E.et al. 1996. Novel transcribed sequences represented in the complex genomic region 5q13. Acta Biochimica et Biophysica 1308(2), pp. 97-102. (10.1016/0167-4781(96)00097-8)
Nawrotzki, R., Blake, D. J. and Davies, K. E. 1996. The genetic basis of neuromuscular disorders. Trends in Genetics 12(8), pp. 294-298. (10.1016/0168-9525(96)10033-0)
Theodosiou, A. M.et al. 1996. A member of the MAP kinase phosphatase gene family in mouse containing a complex trinucleotide repeat in the coding region. Human Molecular Genetics 5(5), pp. 675-684. (10.1093/hmg/5.5.675)
Blake, D. J.et al. 1996. Isoform diversity of dystrobrevin, the murine 87-kDa postsynaptic protein. Journal of Biological Chemistry 271(13), pp. 7802-7810. (10.1074/jbc.271.13.7802)
Zuelling, R. A.et al. 1996. Cloning of the rat utrophin and characterization of an alternate transcript. Journal of Muscle Research and Cell Motility 17(1), pp. 110-110.
Zuellig, R. A.et al. 1996. Cloning of the rat utrophin and characterization of an alternate transcript. Journal of Muscle Research and Cell Motility 17(1), pp. 110-110.
Blake, D. J., Tinsley, J. M. and Davies, K. E. 1996. Utrophin: a structural and functional comparison to dystrophin. Brain Pathology 6(1), pp. 37-47. (10.1111/j.1750-3639.1996.tb00781.x)
Ponting, C. P.et al. 1996. ZZ and TAZ: new putative zinc fingers in dystrophin and other proteins. Trends in Biochemical Sciences 21(1), pp. 11-13. (10.1016/S0968-0004(06)80020-4)

1995

Millwood, I. Y.et al. 1995. Two polymorphic dinucleotide repeats in the rat dystrophin gene, including the conserved 3' UTR repeat. Mammalian Genome 6(9), pp. 668-669.
Davies, K. E., Tinsley, J. M. and Blake, D. J. 1995. Molecular analysis of Duchenne muscular dystrophy: past, present, and future. Annals of the New York Academy of Sciences 758, pp. 287-296. (10.1111/j.1749-6632.1995.tb24834.x)
Blake, D. J.et al. 1995. G-Utrophin, the autosomal homologue of dystrophin Dp116, is expressed in sensory ganglia and brain. Proceedings of the National Academy of Sciences of the United States of America 92(9), pp. 3697-3701. (10.1073/pnas.92.9.3697)
Blake, D. J.et al. 1995. Coiled-coil regions in the carboxy-terminal domains of dystrophin and related proteins: potentials for protein-protein interactions. Trends in Biochemical Sciences 20(4), pp. 133-135. (10.1016/S0968-0004(00)88986-0)
Pasquini, F.et al. 1995. The effect of glucocorticoids on the accumulation of utrophin by cultured normal and dystrophic human skeletal muscle satellite cells. Neuromuscular Disorders 5(2), pp. 105-114. (10.1016/0960-8966(94)00042-8)

1994

Brookes, A. J.et al. 1994. Cloning the shared components of complex DNA resources. Human Molecular Genetics 3(11), pp. 2011-2017. (10.1093/hmg/3.11.2011)
Tinsley, J. M.et al. 1994. Increasing complexity of the dystrophin-associated protein complex. Proceedings of the National Academy of Sciences of the United States of America 91(18), pp. 8307-8313.
Schofield, J. N.et al. 1994. Apo-dystrophin-1 and apo-dystrophin-2, products of the Duchenne muscular dystrophy locus: expression during mouse embryogenesis and in cultured cell lines. Human Molecular Genetics 3(8), pp. 1309-1316. (10.1093/hmg/3.8.1309)
Davies, K.et al. 1994. Possible roles for utrophin in gene-therapy of duchenne muscular-dystrophy. Journal of Cellular Biochemistry 1994(18A), pp. 188-188.
Blake, D. J., Tinsley, J. M. and Davies, K. E. 1994. The emerging family of dystrophin-related proteins. Trends in Cell Biology 4(1), pp. 19-23. (10.1016/0962-8924(94)90034-5)

1993

Pearce, M.et al. 1993. The utrophin and dystrophin genes share similarities in genomic structure. Human Molecular Genetics 2(11), pp. 1765-1772. (10.1093/hmg/2.11.1765)
Tinsley, J. M.et al. 1993. Dystrophin and related proteins. Current Opinion in Genetics & Development 3(3), pp. 484-490. (10.1016/0959-437X(93)90124-8)
Tinsley, J. M., Blake, D. J. and Davies, K. E. 1993. Apo-dystrophin-3: a 2.2kb transcript from the DMD locus encoding the dystrophin glycoprotein binding site. Human Molecular Genetics 2(5), pp. 521-524. (10.1093/hmg/2.5.521)
Blake, D. 1993. Dystrophin and dystrophin-related proteins: a review of protein and RNA studies. Neuromuscular Disorders 3(1), pp. 5-21. (10.1016/0960-8966(93)90037-K)

1992

Blake, D. J.et al. 1992. Characterization of a 4.8kb transcript from the Duchenne muscular dystrophy locus expressed in Schwannoma cells. Human Molecular Genetics 1(2), pp. 103-109. (10.1093/hmg/1.2.103)
Tinsley, J. M.et al. 1992. Primary structure of dystrophin-related protein. Nature 360(6404), pp. 591-593. (10.1038/360591a0)
thi Man, N.et al. 1992. Utrophin, the autosomal homologue of dystrophin, is widely-expressed and membrane-associated in cultured cell lines. FEBS Letters 313(1), pp. 19-22. (10.1016/0014-5793(92)81174-K)

1991

Coleman, M. P.et al. 1991. Genetic and physical mapping around the properdin P gene. Genomics 11(4), pp. 991-996. (10.1016/0888-7543(91)90024-9)
Sellar, G. C., Blake, D. J. and Reid, K. B. 1991. Characterization and organization of the genes encoding the A-, B- and C-chains of human complement subcomponent C1q. The complete derived amino acid sequence of human C1q. Biochemical Journal 274(2), pp. 481-490.
Sellar, G. C., Blake, D. J. and Reid, K. B. 1991. Characterization and organization of the genes encoding the A-, B- and C-chains of human complement subcomponent C1q. The complete derived amino acid sequence of human C1q. Biochemical Journal 274(2), pp. 481-490. (10.1042/bj2740481)

1989

Knott, V., Blake, D. J. and Brownlee, G. G. 1989. Completion of the detailed restriction map of the E.coli genome by the isolation of overlapping cosmid clones. Nucleic Acids Research 17(15), pp. 5901-5912. (10.1093/nar/17.15.5901)
Blake, D. J. and Brownlee, G. 1989. Deletion of the mcf.2 transforming gene in 2 hemophilia-b inhibitor patients. Cytogenetics and Cell Genetics 51(1-4), pp. 963-963.
Blake, D. J. and Brownlee, G. G. 1989. Deletion of the MCF.2 transforming gene in 2 Hemophilia-B inhibitor patients [Abstract]. Cytogenetics and Cell Genetics 51(1-4), pp. 963.

1988

Anson, D.et al. 1988. Nullisomic deletion of the mcf.2 transforming gene in two haemophilia B patients.. EMBO Journal 7(9), pp. 2795-2799.
Anson, D. S.et al. 1988. Nullisomic deletion of the mcf.2 transforming gene in two haemophilia B patients. EMBO Journal 7(9), pp. 2795-2799.

1987

Blake, D. J., Knott, V. and Brownlee, G. 1987. A random cosmid contig approach to gene-mapping. Cytogenetics and Cell Genetics 46(1), pp. 581-581.
Blake, D. J., Knott, V. and Brownlee, G. 1987. A random cosmid contig approach to gene-mapping [Abstract]. Cytogenetics and Cell Genetics 46(1-4), pp. 581. (10.1159/000316989)

Bioinformatics (MSc) - Introduction to Bioinformatics

Medicine (MBBCh) - Case Based Learning (CBL) Facilitator

Medicine (MBBCh) - Platform for Clinical Sciences Tutor

Medical Pharmacology (BSc) and Biological Sciences (BSc) - Profession Training Year (PTY) supervisor

Transcription factors in neurodevelopmental disorders

Recent advances in neuropsychiatric genetics have identified biological processes and risk variants that are regulated by key schizophrenia-associated transcription factors (TFs) and chromatin writers (collectively transcriptional regulators) that are also causally implicated in a range of neurodevelopmental disorders through rare, exonic mutations. For many common disorders, altered binding of transcriptional regulators to non-coding variants can directly mediate disease risk, modulate gene expression and ultimately shape phenotypes. The major aim of this project is to define the genomic targets for selected schizophrenia-associated transcriptional regulators such as TCF4 (Transcription Factor 4) in cell models and tissue two differentiated human using chromatin-immunoprecipitation and next generation sequencing (ChIP-seq). In collaboration with Dr Matt Hill (https://www.cardiff.ac.uk/people/view/62738-hill-matt), we have used the near base-pair resolution of ChIP-seq to discover regulatory binding sites in genomic loci associated with schizophrenia and other common neurodevelopmental disorders and derive binding-site motifs for each TF where appropriate (https://orca.cf.ac.uk/107566/1/sbx164.pdf). We are also interested in Pitt-Hopkins Syndrome (PTHS) - a rare neurodevelopmental disorder caused by heterozygous TCF4 mutations. We are currently trying to determine the role of PTHS-associated mutations on the function of TCF4 in a range of model systems.

TCF4 in Fuchs' endothelial corneal dystrophy (FECD)

The cornea, the clear window at the front of the eye, is one of the most transplanted tissues worldwide with nearly 50,000 corneal grafts performed in 2015 in the USA alone. FECD affects approximately 4% of people over the age of 40 and is the most common indication for corneal graft surgery in the USA. Over time, cell loss and painful blistering cause changes in the transparency of the cornea and progressive loss of vision leading to blindness in the most severe cases. FECD is an inherited condition with approximately 80% of cases being associated with trinucleotide repeat expansion in an intron of the TCF4 gene. As described above, TCF4 has a regulatory function and can act as a molecular switch to turn other genes on and off by binding to specific sites in the genome. In collaboration with Prof Andrew Quantock (https://www.cardiff.ac.uk/people/view/38248-quantock-andrew) and Dr Matt Hill, we have shown that small alterations in the levels of TCF4 can have dramatic effects on cell function and cell survival. To improve our understanding of the molecular basis for FECD and to find new drug targets to treat this disorder, we are using the latest genetic techniques and cell models to identity the genes and processes that are controlled by TCF4 in corneal endothelial cells.

Microglial biology

The majority of risk genes for Alzheimer’s Disease (AD) are highly expressed in microglia - a specialized population of resident macrophage-like cells found in brain. Genetic risk for AD is concentrated in specific macrophage and microglial transcriptional networks that are regulated by a handful of transcription factors (TFs) including PU.1 and MEF2C. In collaboration with Dr Matt Hill (https://www.cardiff.ac.uk/people/view/62738-hill-matt), we are studying how these TFs regulate gene expression and AD risk using proteomic and genomic techniques. We are also using proximity-labelling proteomics to study the function of selected genes that form part of the AD-risk network in microglia. These projects will provide mechanistic insights into the molecular process involved in AD pathogenesis and will be used to find new drug targets to treat this disorder.

Organisation of the junctional sarcoplasmic reticulum (jSR) in striated muscle

The jSR is a specialised region of the sarcoplasmic reticulum of muscle cells that concentrates resident and peripheral proteins to regulate calcium release and excitation-contraction coupling. To understand how the jSR is assembled we used immunoaffinity purification and mass spectrometry to identify proteins complexes that are targeted to the jSR in cardiac and skeletal muscle. We found that the myospryn complex interacts with ryanodine receptors (the major calcium release channel of the SR) and other components of the jSR in cardiac muscle (https://www.nature.com/articles/s41598-017-06395-6). We are currently using a range of molecular tools to understand the role of the myospryn complex during the assembly of jSR and how these processes are altered in heart disease.

Professor Derek Blake

Overview

Biography

Publications

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