Professor David M. Hunt
Professor of Molecular Genetics. BSc Zoology, PhD Genetics
Institute of Ophthalmology Tel: 020 7608 6820
11-43 Bath Street Fax: 020 7608 6863
London EC1V 9EL Email: d.hunt@ucl.ac.uk
understanding of this process and how pigments are differentially sensitive
Summary of current research interests to different wavelengths of light is fundamental to our understanding of
Our research programme has two inter-related components, the molecular
the visual process. Many retinal disease genes encode proteins that are
evolution and structure of visual pigments, and the identification and
integral to the pathway of phototransduction, although others encode more
functional analysis of retinal disease genes. The capture of photons by
widely expressed genes. Whatever the mechanism, it is vitally important to
visual pigments is the first step in phototransduction, the process that
understand the development of disease pathology in terms of mutant gene
converts a photon of light into an electrical signal within the retina, and the
action and its effect on protein function.
Key achievements Evolution of scotopic and photopic vision
• The molecular evolution of “red” and “green” sensitive visual pigments in Day light vision preceeded dim light vision in evolution. Cone
New World and Old World primates photoreceptors are responsible for the former and rod photoreceptors for
• Cloning, expression pattern and mechanism of spectral shift in avian the latter. Both contain cell-specific components of phototransduction. Data
ultraviolet-sensitive visual pigments from agnathans suggest that a rod visual pigment is not present and current
• Molecular basis for the spectral shifts in the evolution of visual pigments work is directed towards identifying other phototransduction genes in
in the flock of cottoid fish in Lake Baikal lampreys and other ancient vertebrates.
• Molecular biography: the classification of John Dalton’s red-green colour
blindness as deuteranopia Structure/function studies of shortwave-sensitive visual pigments
• Identification of disease genes in several retinal dystrophies, including The focus is on shortwave-sensitive cone pigments. These exist in two
retinal guanylate cyclase, RIMS1, PROM1 and KCNV2. spectrally distinct forms in different vertebrate species, with peak sensitivities
in either the ultraviolet (<390nm) or violet (390-440nm) regions of the
Research Projects spectrum. Phylogenetics indicates that ultraviolet-sensitive (UVS) pigments
Molecular evolution and spectral tuning of vertebrate visual pigments were ancestral and functional analysis suggests that UVS pigments have
The light-sensitive visual pigments in the photoreceptors of the retina an unprotonated Schiff base. We have already shown that the shift to
provide the first step in the visual process. They are composed of an opsin violet sensitivity in most cases involves a single amino acid substitution at
protein linked via a Schiff base to retinal, a derivative of vitamin A. Five one of just two sites. Current studies are directed towards a more complete
classes of pigment are found amongst the vertebrates, a rod class with understanding of the molecular mechanisms for these changes, with the
peak sensitivity (λmax) between 480 and 520 nm, and four cone classes, aim of obtaining detailed information about molecular conformation that
longwave-sensitive with λmax between 490 and 570 nm, middlewave- can be used in the determination of the three dimensional structure of these
sensitive with λmax between 480 and 530 nm, shortwave-sensitive type 1 cone pigments.
with λmax between 355 and 440 nm, and short wave-sensitive type 2 with
λmax between 410 and 490 nm. Variation in spectral tuning of pigments Identification and functional analysis of retinal disease genes
is related to fitness and arises from amino acid substitutions in the opsin Hereditary retinal disease and age-related macular degeneration (AMD)
protein. Our studies have charted the molecular evolutionary changes are the major causes of visual loss, accounting for well over 50% of all blind
in rod and cone pigments from many species that include lampreys, fish registrations in the developed world. In most cases, the loss or absence
(deep-sea, antarctic, lacustrine), birds (passerines, parrots, birds of prey, of photoreceptors is the primary cause of blindness. In collaboration with
seabirds) and mammals (monotremes, marsupials, rodents, primates). clinical colleagues at Moorfields Eye Hospital, a variety of strategies for the
mapping and identification of retinal disease genes have been used, plus
screening for new mutations in previously identified disease genes.
The disorders studied included several cone, cone-rod and macular
dystrophies, blue cone monochromatism, achromatopsia, oligocone
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Professor David Hunt
trichromacy, and cone dystrophy with supernormal rod ERG, with
mutations identified in retinal guanylate cyclase, RIMS1, PROM1, KCNV2
and the cone cGMP-gated channel proteins. Animal models using gene
targeting methods have now been developed for cone-rod disorders with
knock-in mutations in GCAP1 and retGC1.
Splicing factor mutant genes in retinitis pigmentosa
Retinitis pigmentosa (RP) can be caused by mutations in a number of
different genes and may show dominant, recessive or X-linked inheritance.
In many cases, the “disease gene” is specifically expressed in the retina but
there are exceptions to this, the most surprising being mutations in three
splicing factor genes, PRPF31, HPRP3 and PRPC8. These genes encode
components of the ubiquitous mRNA splicing machinery. Nevertheless,
mutations in these genes cause dominant RP with the defect entirely
limited to the retina; the challenge is therefore to understand why
pathology is restricted to the retina. Our studies with PRPF31 implicate
abnormal trafficking of mutant protein as a major cause of the disease
process, most likely arising from abnormal folding of the mutant protein
which is seen in vitro as a reduction in protein solubility. Current work is
focused on the splicing efficiency of mutant proteins, and on interactions
with other components of the splicing apparatus.
Publications Click here for complete publications list Fundings:
Davies, W. L., Carvalho, L. S., Cowing, J. A., Beazley, L. D., Hunt, D. M. and
• Australian Research Council
Arrese, C. A. (2007) Visual pigments of the platypus: a novel route to • Biotechnology and Biological Research Council
mammalian colour vision. Current Biology 17, R161-163. • British Eye Research Foundation
• British Retinitis Pigmentosa Society
• Fight for Sight
Wu, H., Cowing, J. A., Michaelides, M., Wilkie, S. E., Jeffery, G., Jenkins,
• Foundation Fighting Blindness
S. A., Nazari, M. M. Y., Mester, V., Bird, A. C., Robson, A. G., Holder, G. E., • Leverhulme Trust
Moore, A. T., Hunt, D. M. and Webster, A. R. (2006) Mutation in the gene • Macular Disease Society
• Wellcome Trust
KCNV2, encoding a voltage-gated potassium channel subunit cause
“cone dystrophy with a supernormal rod electroretinogram” in humans. Research Group:
American Journal of Human Genetics 79, 574-579. • Livia Carvalho
• Jill Cowing
Cowing, J. A., Poopalasundaram, S., Wilkie, S. E., Robinson, • Wayne Davies
• Ambreen Kalhoro
P. R., Bowmaker, J. K. and Hunt, D. M. (2002) The molecular mechanism
• Samantha Mohun
for the spectral shifts between vertebrate ultraviolet- and violet-sensitive • Susan Wilkie
cone visual pigments. Biochemical Journal 367, 129-135.
Collaborators:
Wilkie, S. E.,Newbold, R. J., Raux, E., Walker, C. E., Stinton, I., • Professor Robin Ali
• Dr Cathy Arrese, University of Western Australia
Visvanathan, R., Hurley, J. B., Bhattacharya, S. S., Warren, • Professor Lyn Beazley, University of Western Australia
M. J. and Hunt, D. M. (2000) Functional characterisation of missense • Professor Shomi Bhattacharya
mutations at codon 838 in retinal guanylate cyclase correlates with • Professor Jim Bowmaker
• Dr Venkatesh Byrappa, University of Singapore
disease severity in patients with autosomal dominant cone-rod dystrophy.
• Dr Karen Carleton, University of New Hampshire
Human Molecular Genetics 9, 3065-3073. • Professor Shaun Collin, University of Queensland
• Professor Russell Foster, University of Oxford
• Professor Glen Jeffery
Wilkie, S. E., Robinson, P. R., Cronin, T. W., Popoolasundarum,
• Professor Tony Moore
S., Bowmaker, J. K. and Hunt, D. M. (2000) Spectral tuning of avian • Dr Phyllis Robinson, University of Maryland
violet- and ultraviolet-sensitive visual pigments. • Dr Martin Stocker
Biochemistry 39, 7895-7901. • Dr Anne Trezise, University of Queenland
• Professor Martin Warren, University of Kent
• Mr Andrew Webster
• Dr Kang Zhang, University of Utah
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