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Research Overview

The Eye Genetics Unit, led by Professor Robyn Jamieson, is focused on genomic, stem cell and genetic therapy applications for maximization of the genetic diagnostic rate and new therapies for blinding genetic eye diseases. In our research studies we investigate patient-derived human induced pluripotent stem cells differentiated to retinal organoids, to determine underlying disease mechanisms and test new genetic therapies. We use CRISPR/Cas9 gene editing to introduce or correct mutations, as well as AAV-mediated genetic therapy strategies. Transcriptomic and proteomic investigations are undertaken to determine the underlying disease mechanisms and to inform development of new gene and pharmacological therapy approaches.

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Genetic eye conditions, such as inherited retinal diseases, were difficult to genetically diagnose and considered untreatable for many years. Excitingly, our genomic research studies have successfully led to genetic diagnoses and understanding of disease mechanisms. Our new frontier is development of novel genetic therapies to rescue vision in these disorders.”

Prof Robyn Jamieson
Head, Eye Genetics

Lab Head

Robyn Jamieson

Robyn Jamieson

Head, Eye Genetics Unit

Head of the Eye Genetics Unit

View full bio

Team Members

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Amin Sabri
Research officer

Research Projects

Genetic retinal diseases affect approximately 1 in 1,000 individuals, or more than five million people worldwide, and are the commonest cause of blindness in working-age people. They are caused by abnormality of photoreceptor (PR) cells, with retinal pigment epithelial (RPE) cells also affected. The photoreceptors contain outer segments which are specialised sensory cilia. Consistent with other studies, over two-thirds of the variants we detect are in genes encoding proteins involved in cilia structure or sensory functions of the PRs, and/or affect genes only expressed in the retina. The human retina is an inaccessible organ for functional biological assays, so human induced pluripotent stem cell (hiPSC)-derived retinal organoids and RPE cells provide an exciting solution system for improved diagnosis and for assessment of therapies in these conditions.

Using patient-derived hiPSC-retinal organoids and RPE and application of RNA-based analyses, we are investigating non-canonical splice site, as well as missense variants in RPGR, IQCB1, RPE65, PDE6B and other retinal disease genes. Control hiPSC lines are also used to engineer in variants of interest using CRISPR/Cas9 gene editing approaches. Single cell transcriptomic studies in retinal organoids are used to interrogate pathways affected in these retinal conditions. This facilitates clearcut variant interpretation and helps towards mechanistic understanding of disease and development of new therapies for these disorders.

The eye is an ideal organ to apply advanced genome engineering, AAV, stem cell and other therapeutic technologies, due to its relatively small size (so less demand on the scale-up of the technology), and its ease of accessibility. We have selected two retinal dystrophies for development of novel gene replacement therapies, due to their suitable gene size for this approach. Gene replacement and promoter construct have been created for use in an AAV vector construct designed for subretinal delivery. We are testing these therapeutic constructs in our mouse models, and patient-derived retinal organoids. Gene-editing approaches are also in use for other variants where this is applicable. This work paves the way for genetic therapies for patients in NSW and other Australian states for genetic retinal diseases suitable for clinical trials.

While some AAV serotypes are in use for subretinal delivery in retinal diseases, there is a need for improved precision and efficacy through delivery of therapeutic constructs to the correct cells, and intravitreal delivery would add additional safety. We use a primary human retinal explant culture system for selection and investigation of novel retinal AAV capsids. All of the advances we make in AAV and other delivery technologies in this project, will be applicable for the various forms of retinal dystrophies present in affected patients.

We recently identified a gain of function mutation in a novel genetic retinal disease gene, ALPK1, causative of the newly identified ROSAH (Retinopathy, Optic oedema, Splenomegaly, Anihidrosis, Headaches) syndrome. ALPK1 encodes an atypical protein kinase. ALPK1 is localised to the transition zone of the connecting cilium of the photoreceptors, and in the innate immunity system, acts as a pattern recognition receptor (PRR) impacting phospho-signalling and downstream NFkB mediated inflammation. In this project, further mechanistic studies will be pursued using a multi-omics approach for phenotype comparisons, which is powerful in revealing dynamics and controlling factors in biological pathways. Transcriptomic, proteomic and phosphoproteomic studies will be undertaken, along with evaluation of modulation of the ALPK1 pathway in our model systems using CRISPR/Cas9 gene editing approaches.

Our research genomic strategies have successfully led to availability of clinical genomic diagnostic testing in the genetic retinal diseases, with our collaborators at The Children’s Hospital at Westmead, Sydney Children’s Hospitals Network. These genomic diagnoses provide a strong foundation for accurate groupings in our natural history studies in preparation for clinical trials, with our collaborators at The Children’s Hospital at Westmead, Sydney Children’s Hospitals Network and Save Sight Institute, Sydney Eye Hospital.

Congenital cataracts, disorders of the anterior segment of the eye, glaucoma and very small eyes are also debilitating ocular conditions, with previous low genetic diagnostic detection rates. Our research genomic studies in these disorders are proving successful in identifying the most useful strategies to maximise genetic diagnosis. Functional genomic studies are also used to increase the diagnostic yield in these disorders, and have potential for further therapy development for the associated visual impairment.

Publications

ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder

Williams LB, Javed A, Sabri A, et al. Genet Med. 2019;21(9):2103-2115. doi:10.1038/s41436-019-0476-3

NMNAT1 variants cause cone and cone-rod dystrophy.

Nash BM, Symes R, Goel H, et al. Eur J Hum Genet. 2018;26(3):428-433. doi:10.1038/s41431-017-0029-7

Revealing hidden genetic diagnoses in the ocular anterior segment disorders.

Ma AS, Yousoof S, Grigg JR, Flaherty M, Minoche AE, Cowley M, Nash BM, Ho G, Gayagay T, Lai T, Farnsworth E, Hackett EL, Fisk K, Wong K, Holman KJ, Jenkins G, Cheng A, Martin F, Karaconji T, Elder JE, Enriquez A, Wilson M, Amor D, Stutterd CA, Kamien B, Nelson J, Dinger ME, Bennetts B, Jamieson RV. Genetics in Medicine, 2020, Jun 5.

Gene selection for the Australian Reproductive Genetic Carrier Screening Project (“Mackenzie’s Mission”).

Kirk EP, Ong R, Boggs K, Hardy T, Righetti S, Kamien B, Roscioli T, Amor D, Bakshi M, Chung C, Colley A, Jamieson RV, Liebelt J, Ma A, Pachter N, Rajogopalan S, Ravine A, Wilson M, Caruana J, Archibald A, Casella R, Davis M, Edwards S, McGaughran J, Newson A, Laing N, Delatycki M. European Journal of Human Genetics, 2020, Jul 16

Biomarkers in Usher Syndrome: ultra-widefield fundus autofluorescence and optical coherence tomography findings and their correlation with visual acuity and electrophysiology findings.

Mustafic N, Ristoldo F, Nguyen V, Fraser CL, Invernizzi A, Jamieson RV, Grigg JR. Documenta Ophthalmologica. 2020 Apr 2. PMID: 32240425.

Schofield D, Zeppel MJB, Staffieri S, Shrestha RN, Jelovic D, Lee E, Jamieson RV. Reproductive Biomedicine and Society Online, 2020, 10:37-45.

Cost effectiveness of the use of preimplantation genetic diagnosis for retinoblastoma survivors.

Outcome measures in Juvenile X-linked Retinoschisis: A systematic review.

Grigg JR, Fraser CL, Hooper CY, Cornish EE, McCluskey PJ, Jamieson RV. Eye (Lond). 2020 Apr 20.

Neurofibromatosis Type 1: review and update on emerging therapies.

Williams LB#, Javed A#, Sabri A#, Morgan DJ#, Huff CD, Grigg JR, Ting Heng X, Khng A, Hollink IHIM, Morrison MA, Owen LA, Anderson K, Kinard K, Greenlees R, Novacic D, Sen HN, Zein WM, Rodgers G, Vitale AT, Haider NB, Hillmer AM, Ng PC, Shankaracharya, Cheng A, Zheng L, Gillies M, von Slegtenhorst M, van Hagen PM, Missotten TOAR, Farley GL, Polo M, Malatack J, Curtin J, Martin F, Arbuckle S, Alexander SI, Chircop M, Davila S, Digre K, Jamieson RV##, DeAngelis MM### Equal First Authors; ##Equal Last Authors, Genetics in Medicine, 2019, Sep;21(9):2103-2115. Epub 2019 Apr 10.

Phenotype-genotype correlations and emerging pathways in ocular anterior segment dysgenesis.

Ma AS, Grigg JR, Jamieson RV. Human Genetics, 2019, Sep; 138(8-9):899-915. Epub 2018 Sep 21. Epub ahead of print.

Investigation of clinically relevant germline variants detected by next generation sequencing in childhood cancer patients.

Sylvester D, Chen Y, Jamieson RV, Dalla-Pozza L, Byrne JA. Journal of Medical Genetics. 2018 Dec;55(12):785-793.

Investigative Ophthalmology and Visual Science

Shaaban S, MacKinnon S, Andrews C, Staffieri SE, Maconachie GD, Chan W-M, Whitman, MC, Morton SU, Yazar S, MacGregor S, Elder JE, Traboulsi EI, Gottlob I, Hewitt AW, Strabismus Genetics Research Consortium (Jamieson RV), Hunter DG, Mackey DA, Engle EC. 2018, August; 59 (10): 4054-4064. PMID

New mutations in GJA8 expand the phenotype to include total sclerocornea

Ma AS, Grigg JR, Prokudin I, Flaherty M, Bennetts B, Jamieson RV. Clinical Genetics, 2018 Jan;93(1):155-159. Epub 2017 Sep 8.

Sporadic and familial congenital cataracts: mutational spectrum and new diagnoses using next-generation sequencing.

Ma AS, Grigg JR, Ho G, Prokudin I , Farnsworth E, Holman K, Cheng A, Billson FA, Martin F, Fraser C, Mowat D, Smith J, Christodoulou J, Flaherty M, Bennetts B, Jamieson RV. Human Mutation, 2016 Apr;37(4):371-84.

Changing patterns in paediatric optic atrophy aetiology: 1979 to 2015.

Zheng L, Do H, Sandercoe T, Jamieson R, Grigg J. Clinical and Experimental Ophthalmology, 2016 Sep;44(7):574-581.

Masquerade macular exudation in Mallatia Leventinese.

Ewe SYP, Jamieson RV, Chang AA. Canadian Journal of Ophthalmology, 2016, Feb; 51 (1):e27-29.

Mutations in SIPA1L3 cause eye defects through disruption of cell polarity and cytoskeleton organization.

Greenlees R*, Mihelec M*, Yousoof S*, Speidel D, Wu SK, Rinkwitz S, Prokudin I, Perveen R, Cheng A, Ma A, Nash B, Gillespie R, Loebel DA, Clayton-Smith J, Lloyd IC, Grigg JR, Tam PP, Yap AS, Becker TS, Black GC, Semina E, Jamieson RV. (*Equal first authors) Human Molecular Genetics, 2015; 24(20): 5789-5804.

Primary congenital glaucoma outcomes: lessons from 23 years of follow-up.

Zagora SL, Funnell CL, Martin FJ, Smith JEH, Hing S, Billson FA, Veillard A, Jamieson RV, Grigg JR American Journal of Ophthalmology, 2015 Apr;159(4):788-96.

Prokudin I, Li D, He S, Guo Y, Goodwin L, Wilson M, Rose L, Tian L, Shen Y, Liang J, Keating B, Xu X, Jamieson RV, Hakonarson H.

Prokudin I, Li D, He S, Guo Y, Goodwin L, Wilson M, Rose L, Tian L, Shen Y, Liang J, Keating B, Xu X, Jamieson RV, Hakonarson H Clinical and Experimental Ophthalmology. 2015 Mar;43(2):132-8.

Major Achievements

2011

SOX2 mutation associated with isolated infertility. Individuals with mutations in SOX2 usually have severe eye anomalies and some also have pituitary abnormalities. This was the first recognition that mutation in SOX2 may cause pituitary abnormalities and infertility, even in the absence of eye abnormalities. Article.

2012

Unique Australian eye disease family found to have a novel mutation in TUBB2B. The eye and brain phenotype in this family pinpointed the divergent roles of ß-tubulin subtypes in microtubule dynamics and axon guidance. Article.

2013

Whole-exome sequencing successful for disease gene identification in developmental eye disease. These eye disorders are markedly genetically heterogeneous and our study demonstrated the value of whole-exome sequencing for genetic diagnosis in these conditions. Article.

2014

Australian families with balanced structural variants lead to novel candidate disease gene identification in cerebral and other disorders. A mate paired whole-genome sequencing strategy was undertaken with our Genome Institute of Singapore collaborators, and novel candidate disease genes identified that may contribute to schizencephaly and developmental delay.

2015

SIPA1L3 novel disease gene identification and characterisation. Human, zebrafish and mouse studies showed that SIPA1L3 has a critical role in epithelial cell morphogenesis, polarity, adhesion and cytoskeletal organisation.

2016

Australian-first of translation of our research genomic testing for genetic eye diseases to clinical diagnostic testing, through our collaboration with the Sydney Genome Diagnostics Laboratory within the Western Sydney Genetics Program at The Children’s Hospital at Westmead. As we head to the new era of genetic therapies for some of these conditions, attainment of genetic diagnoses for patients is critical. For most of the new clinical trials or therapies, patients are required to have a genetic diagnosis to be eligible for the therapy.

2019

ALPK1 novel retinal disease gene identification and characterisation. The first to report a newly defined retinal dystrophy syndrome and its causative disease gene ALPK1, opening up a new disease mechanism pathway.

2020

A multidisciplinary team (MDT) approach encompassing phenotypic, genomic, variant, and segregation analysis to maximise the genomic diagnostic rate.