MRC Mouse Network Jan 2012 Mouse eyes and vision research consortium Prof Marcela Votruba PhD...

MRC Mouse Network Jan 2012

Mouse eyes and vision research consortium

Prof Marcela Votruba PhD FRCOphth

Prof Ian Jackson PhD


Ocular Genetics

4 newly visually impaired children each day in UKEvery day 100 people in the UK start losing their sight


• 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


• 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!


Investigators Cardiff:

PI: Professor Marcela Votruba: optic neuropathies & mitochondrial disease Professor James E Morgan: glaucomasDr Jez Guggenheim: myopia and refractive errors

Edinburgh: PI: Professor Ian Jackson: eye phenotype analyses on mutagenised miceProfessor David FitzPatrick: developmental eye disordersProfessor John West: cornea

Oxford: Professor Russsell Foster: circadian clocksProfessor Robert E MacLaren: inherited retinal disease & retinal degeneration

Bristol:Professor Andrew Dick: inflammatory eye diseasesDr Denize Atan: retinal development

Southampton: Prof Andrew Lotery: age related macular degeneration

Leeds: Professor Chris Inglehearn: retinitis pigmentosa


Themes

• Ocular development• Ocular ageing• Neurodegeneration

• Cornea• Retina• Optic nerve


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


Principal Aims

• To identify the pathways thatunderlie normal eye function andhow these are disrupted in disease

• To provide platforms fortherapeutic developments

• To integrate basic scientists andclinicians and human geneticists


Objectives

• To establish novel phenotyping infrastructure at each centre according to expertise

• 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 process lines in parallel in collaborative centres, depending on disease model

• To undertake groundbreaking research with translational impact

• To organize a collaborative meeting in early 2012 to prioritize genes and discuss models and new phenotyping

• To attract additional funding


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


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.


Translational impact

MRC Mouse Network Jan 2012 Mouse eyes and vision research consortium Prof Marcela Votruba PhD...

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