Shiels Lab

Alan Shiels PhD, Professor, Ophthalmology & Visual Sciences, and Genetics

Dr. Shiels’ profile

Research Overview

Our research focuses on the molecular genetic mechanisms underlying lens development and cataract(s). Despite surgical treatment, age-related forms of cataract remain a leading cause of low vision and blindness worldwide. Using genome-wide mapping and targeted/exome sequencing techniques we have discovered several genes underlying inherited forms of early-onset (pediatric) cataract and other associated ocular or systemic disorders in humans (Table 1). Genes underlying relatively rare forms of inherited cataract have also been associated with much more common forms of age-related cataract – providing molecular genetic links between lens development and aging. Currently, we are characterizing several strains of mutant mice in order to model the pathogenic mechanisms underlying cataract development in humans (Table 2). Results from these studies will advance understanding of lens and anterior eye development in health versus disease and contribute to the discovery of therapeutic targets for cataract.

Molecular Genetic Mechanisms underlying Lens Development and Cataract

Biomedical context: The crystalline lens is critical for anterior eye development and refractive vision in vertebrates. Loss of lens transparency or cataract(s) is frequently acquired with aging and, despite surgical treatment, age-related cataract remains a leading cause of visual impairment (low vision and blindness) worldwide. Cataract may also be inherited as a classical Mendelian trait that usually presents with an early-onset (pediatric). Congenital and infantile forms of cataract pose a clinically important cause of deprivation amblyopia (eye wandering), nystagmus (eye oscillation), and strabismus (eye misalignment) and, further, risk post-surgical complications (e.g., glaucoma) and life-long visual impairment. Approximately 200 causative genes have been found for inherited forms of cataract – with or without other ocular and/or systemic abnormalities ( Curiously, genes underlying rare forms of inherited cataract are emerging as susceptibility genes for common forms of age-related cataract – supporting molecular genetic links between lens development and lens aging. In previous human genetic studies, we have discovered mutations and/or variants in several genes underlying inherited or age-related forms of cataract. Based on these findings, we are engaged in three interdisciplinary projects focused on cell-membrane proteins using state-of-the-art molecular genetics and cellular imaging techniques to model cataract gene function and dysfunction in mice.

1. TRPM3 project: TRPM3 belongs to the melastatin sub-family of the transient receptor potential (TRP) superfamily of cation channels that serve as polymodal cellular sensors in critical physiological processes across the animal kingdom including the perception of light, temperature, pressure, and pain. We have shown that mutation of the human TRPM3 gene underlies an inherited form of pediatric cataract with or without glaucoma and anterior eye defects. The overall goal of this project is to determine the role of TRPM3 in development and aging of the lens and other eye tissues – with particular focus on calcium dynamics/signaling.

2. EPHA2 project: EPHA2 belongs to the ephrin receptor sub-family of mammalian receptor tyrosine kinases that elicit diverse signaling pathways in embryonic development, adult tissue homeostasis, and various diseases including cancer. We have shown that mutation of the human EPHA2 gene underlies inherited cataract, whereas, EPHA2 variants are associated with age-related cataract. The overall goal of this project is to determine the role of EPHA2 signaling in lens development and aging – with particular focus on cell pattern-formation/recognition.

3. CHMP4B project: CHMP4B is a core subunit of the phylogenetically conserved (yeast-to-human) endosome sorting complex required for transport-III (ESCRT-III) machinery that facilitates diverse eukaryotic membrane remodeling and scission processes including viral budding, cytokinesis, and membrane repair. We have shown that mutations in the human CHMP4B gene underlie inherited forms of ‘posterior polar’ cataract. The overall goal of this study is to elucidate the role of CHMP4B complexes in lens cell membrane differentiation and function – with particular focus on cell-cell communication.

An Inherited Form of Cataract
Genetic Mapping of Cataract
Mutation Profiling of Cataract
A mouse model of human inherited cataract


  1. Genetic mapping and sequencing studies (phenotype-to-genotype): We have used genome-wide mapping (e.g., SNP markers) and targeted sequencing (e.g., exome) approaches in order to discover causative genes underlying inherited forms of pediatric cataract segregating in families (Table 1). Beyond the predicted genes for cataract, such as those for lens crystallins (CRY) and gap-junction/connexin proteins (GJA3/8), we have discovered several novel genes for cataract including CHMP4B, EPHA2, and TRPM3 (Table 1). We have also identified several germ-line variants and potential somatic variants in EPHA2 that are associated with susceptibility to age-related cataract. Click on the Cat-Map link to view other genes associated with cataract.

    In addition to cataract, we have identified mutations in FRMD7 and EFEMP1 underlying an X-linked form of ideopathic infantile nystagmus and autosomal dominant form of open-angle glaucoma, respectively.

Table 1. Genes underlying inherited cataract and associated ocular or systemic disease discovered in the Shiels lab

Cytogenetic location (Physical co-ordinates)Gene symbolExonDNA changeProtein changeOcular/systemic phenotype
1p36.13 (16124337..16156104, complement)EPHA2Ex17c.2842G>Tp.G948WPosterior polar cataract
1q21.2 (147902795..147915287)GJA8Ex2 Ex2c.142G>A c.262C>Tp.E48K p.P88SZonular nuclear pulverulent cataract Zonular pulverulent cataract
2q33.3 (208121607-208124524, complement)CRYGDEx2c.70C>Ap.P24TCoral-like cataract
2p16.1 (55865967..55924163, complement)EFEMP1Ex5c.418C>Tp.R140WPrimary open angle glaucoma
9q21.12-q21.13 (70529060-71446971, complement)TRPM3Ex4c.195A>Gp.I65MPolymorphic cataract ± glaucoma and/or anterior eye defects
13q12.11 (20138252-20161327, complement)  GJA3Ex2 Ex2 Ex2c.176C>T c.188A>G c.1137insCp.P59L p.N63S p.S380fsX87Nuclear punctate cataract Variable pulverulent cataract Punctate cataract
19q13.33 (48963941..48966879)FTL-IRE5′- IREc.-168G>Tn/aHereditary hyperferritinemia-cataract syndrome
20q11.22 (33811348-33854366)CHMP4B3 3c.386A>T c.481G>Ap.D129V p.E161KPosterior sub-capsular cataract Posterior polar cataract
21q22.23 (43169008-43172810)CRYAA1c.145C>Tp.R49CCentral nuclear cataract
22q12.1 (26599278-26618104, complement)CRYBB16c.728G>Tp.G220XCentral sutural pulverulent cataract
Xq26.2 (132074926..132128022, complement)FRMD76c.425T>Gp.L142RX-linked idiopathic infantile nystagmus
  1. Functional expression studies (genotype-to-phenotype). Currently, we are using several strains of cataract mice that inherit spontaneous or targeted mutations in the genes for (a) an aquaporin water-channel, (b) a cell-junction protein, (c) a chromatin-modifying protein, (d) an ephrin receptor, and (e) a cation channel to elucidate pathogenic mechanisms underlying the development of cataract and certain anterior eye disorders in humans (Table 2). Click on the Cat-Map link to view other mouse models of human cataract.

Table 2. Mouse models of human cataract under investigation in the Shiels lab.

Cytogenetic location (Physical co-ordinates)GeneMutant alleleExon/ IntronDNA changeProtein changeLens Phenotype
3 F1; 3 39.04 cM (89271730..89280951, complement)Efna1tm1JchEx1nullnullLike wild-type
4 D3; 4 73.67 cM (141301221..141329384)Epha2tm1Jrui (neo)Ex5nullnullRefractive disturbance, cell patterning defects
7 B3; 7 28.25 cM (43430099..43435996)Lim2Gt(VICTR48)LexIVS3nullnullRefractive defects and pulverulent opacities
10 D3; 10 76.49 cM (128225810..128231812)  Mip/ Aqp0CatlopEx1c.151G>Cp.A51PDense central opacity, microphakia
10 D3; 10 76.49 cM (128225810..128231812)  Mip/ Aqp0Gt(VICTR20)8LexEx1nullnullPolymorphic opacities
10 D3; 10 76.49 cM (128225810..128231812)  Mip/ Aqp0CatFrIVS3c.607-789delLTRp.203-263delLTRX59Shrivelled, microphakia
17 E1.1; 17 32.57 cM (62602957..62881317, complement)Efna5tm1DdmoExnullnullRefractive disturbance, cell patterning defects
19; 19 B (22137797..22995410)Trpm3tm1AshEx4c.T>GMissense, extensionAnterior polar cataract
19; 19 B (22137797..22995410)tm1Lex/Ori, LEXKO-380Ex21-IVS21nullnullImpaired growth


Cat-Map is an online chromosome map and reference database for inherited and age-related forms of cataract(s) in humans, mice, and other vertebrates maintained by the Shiels lab.

Shiels A, Bennett TM, and Hejtmancik JF. Cat-Map: Putting cataract on the map. Mol Vis (2010)


View all Alan Shiels NCBI publications on PubMed»

Selected Publications

Shiels A. TRPM3_miR-204 – a complex locus for eye development and disease (Review). Hum Genomics 2020; 14:7

Shiels A, Hejtmancik, JF. Biology of inherited cataracts and opportunities for treatment. Ann Rev Vis Sci 2019; 5: 123-149.

Zhou Y, Bennett TM, Shiels A. A charged multivesicular body protein (CHMP4B) is required for lens growth and differentiation. Differentiation 2019; 109:16-27.

Zhou Y, Shiels A. Epha2 and Efna5 participate in lens cell pattern-formation. Differentiation 2018; 102:1-9.

Shiels A, Hejtmancik JF. Mutations and mechanisms in congenital and age-related cataracts. Exp Eye Res 2017; 156:95-102.

Bennett TM, M’Hamdi O, Hejtmancik JF, Shiels A. Germ-line and somatic EPHA2 coding variants in lens aging and cataract. PLoS One 2017; 12(12):e0189881

Bennett TM, Mackay DS, Siegfried CJ, Shiels A. Mutation of the melastatin-related cation channel, TRPM3, underlies inherited cataract and glaucoma. PLoS One 2014; 9(8):e104000.

Shi Y, De Maria A, Bennett TM, Shiels A, Bassnett S. A role for Epha2 in cell migration and refractive organization of the ocular lens. Invest Ophthalmol Vis Sci 2012; 53:551-559.

Shiels A, Bennett TM, Hejtmancik JF. Cat-Map: putting cataract on the map. Mol Vis 2010; 16:2007-2015. (

Shiels A, Bennett TM, Knopf HLS, Maraini G, Li A, Jiao X, Hejtmancik JF. The EPHA2 gene is associated with cataracts linked to chromosome 1p. Mol Vis 2008; 14:2042-2055.

Shiels A, Bennett TM, Knopf HLS, Yamada K, Koh-ichiro Y, Niikawa N, Shim S, Hanson PI. CHMP4B, a novel gene for autosomal dominant cataracts linked to chromosome 20q. Am J Hum Genet 2007; 81:596-606.