Transcript MRC Mouse Eyes&VisionJan2012

Mouse eyes and vision
research consortium
Prof Marcela Votruba PhD FRCOphth
Prof Ian Jackson PhD
MRC Mouse Network Jan 2012
Ocular Genetics
4 newly visually impaired children each day in UK
Every day 100 people in the UK start losing their sight
MRC Mouse Network Jan 2012
•
First early modern
description of a genetic
disease:
– colour blindness, Dalton
1794
• First disease mapped to a
chromosome:
– colour vision deficiency, X
chromosome, Wilson 1911
• First textbook of human
genetics: ‘The human eye
and its genetic disorders’
– Waardenberg 1932
MRC Mouse Network Jan 2012
• First human disease linked
to an autosome:
– autosomal dominant
cataract and the Duffy blood
group, Renwick and Lawler
1963
• First human disease to show
digenic inheritance:
– Retinitis Pigmentosa, Damji
and Allingham 1997
• Gene based therapies!
MRC Mouse Network Jan 2012
Investigators
Cardiff:
PI: Professor Marcela Votruba: optic neuropathies & mitochondrial disease
Professor James E Morgan: glaucomas
Dr Jez Guggenheim: myopia and refractive errors
Edinburgh:
PI: Professor Ian Jackson: eye phenotype analyses on mutagenised mice
Professor David FitzPatrick: developmental eye disorders
Professor John West: cornea
Oxford:
Professor Russsell Foster: circadian clocks
Professor Robert E MacLaren: inherited retinal disease & retinal degeneration
Bristol:
Professor Andrew Dick: inflammatory eye diseases
Dr Denize Atan: retinal development
Southampton:
Prof Andrew Lotery: age related macular degeneration
Leeds:
Professor Chris Inglehearn: retinitis pigmentosa
MRC Mouse Network Jan 2012
Themes
• Ocular development
• Ocular ageing
• Neurodegeneration
• Cornea
• Retina
• Optic nerve
MRC Mouse Network Jan 2012
Gene groups arising from
investigators interests
• Ocular development
– Coloboma
– Anophthalmia/ microphthalmia
– Retinal differentiation/ Prdm family
• Ocular ageing
– Age related macular degeneration
• Cornea
– Wound healing
• Retina
– Retinitis pigmentosa
– Other CRD/ RCD
• Optic nerve
– Glaucoma genes
– Optic neuropathy including
MRC Mouse Network Jan 2012
Principal Aims
• To identify the pathways that
underlie normal eye function and
how these are disrupted in disease
• To provide platforms for
therapeutic developments
• To integrate basic scientists and
clinicians and human geneticists
MRC Mouse Network Jan 2012
Objectives
•
To establish novel phenotyping
infrastructure at each centre
according to expertise
•
To undertake groundbreaking
research with translational
impact
•
To capitalise on results from
UK10K and DDD programmes
of human genetics/genomics at
the Wellcome Trust Sanger
Institute which aim to find genes
involved in human disease by
patient genome sequencing
•
To organize a collaborative
meeting in early 2012 to
prioritize genes and discuss
models and new phenotyping
•
To attract additional funding
•
To process lines in parallel in
collaborative centres,
depending on disease model
MRC Mouse Network Jan 2012
Vision and ocular phenotyping
•
Standard accepted tests:
– Slit lamp
– Ophthalmoscopy
•
Possible additional screens:
– Optokinetic nystagmus/ OKN
– Ocular coherence
tomography/OCT
– electrophysiology/ERG
– fundus autoflorescence/AF
– fundus fluorescein
angiography/FFA
•
Potential future screens
– Pupillary reflex
•
Challenge niche tests
– Circadian phase shift
– More complex
electrophysiology
MRC Mouse Network Jan 2012
Human disease gene identification
• The UK10K project
– sequencing the exomes of 10,000 patients with a range of diseases
– among them will be 100 patients with isolated coloboma and 25
with severe bilateral anophthalmia
• The Deciphering Developmental Disorders programme
– will sequence 12,000 patients with developmental diseases which
will include eye diseases, but the number is not fixed, or known.
Some of the genes identified in these studies will be good
candidates for later rounds of the KO programme.
MRC Mouse Network Jan 2012
MRC Mouse Network Jan 2012
MRC Mouse Network Jan 2012
Translational impact
MRC Mouse Network Jan 2012