Our research focuses on the molecular genetic basis of eye diseases including; cataracts, glaucoma and eye movement disorders, utilizing three complimentary approaches. Mapping studies: Genome-wide markers are being used to map and refine chromosomal loci. Mutation studies: Re-sequencing techniques are being used to identify causative mutations and to develop diagnostic genetic tests. Genotype/phenotype studies: Expression techniques are being used to characterize the underlying pathogenetic mechanisms. Results from these studies will improve understanding of eye development in health versus disease and contribute toward the design of gene-based therapeutics that may help treat or prevent common causes of vision impairment.
Molecular Genetics of Cataract(s)
The crystalline lens plays a central role in vertebrate eye development and refractive vision. Cataract is a light-scattering disorder of the eye lens that despite surgical treatment remains an important cause of visual impairment worldwide. Typically, cataract is acquired with age (>50 years) as a multi-factorial or complex disorder involving genetic and environmental risk factors. However, cataract may also be inherited as a classic Mendelian disorder usually with early onset in either the absence or presence of other ocular and/or systemic abnormalities. Click on the Cat-Map link to view our updated genetic map of cataract. Research in our laboratory aims to identify and characterize molecular genetic determinants of inherited and age-related forms of cataract using two complementary approaches:
1. Mapping and mutation studies (from-phenotype-to-genotype): We have discovered mutations in several genes underlying inherited cataract (Table 1). Click on the Cat-Map link to view other genes associated with cataract. Currently, we are using genome-wide markers to map and refine novel chromosomal loci for inherited cataract. In addition, targeted re-sequencing techniques are being used to: (a) identify causative mutations in positional-candidate genes linked with inherited cataract, (b) develop diagnostic genetic tests for inherited cataract, and (c) identify susceptibility variants in candidate genes associated with age-related cataract.
2. Pathogenetic studies (from-genotype-to-phenotype): Several strains of mice, which inherit spontaneous or targeted mutations in the genes for (a) a water-channel, (b) a cell-junction protein, (c) a chromatin-modifying protein, and (d) a tyrosine-kinase receptor are being used as model systems to elucidate the pathogenic mechanisms underlying the development of cataract and associated eye disorders in humans (Table 2). Click on the Cat-Map link to view other mouse models of human cataract.
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.
Selected Peer-reviewed Papers
- Shiels A, King JM, Mackay DS, Bassnett S. Refractive defects and cataracts in mice
lacking lens intrinsic membrane protein-2. Invest Ophthal Vis Sci (IOVS) 2007; 48:500-
- Shiels A, Hejtmancik JF. Genetic origins of cataract. Arch Ophthalmol 2007; 125:165-
- Brantley MA, Edelstein SL, King JM, Apte RS, Kymes SM, Shiels A. Clinical
phenotypes and treatment outcomes associated with the CFH Y402H variant in AMD.
Am J Ophthalmol (AJO) 2007; 144:404-408.
- 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 (AJHG) 2007; 81:596-606.
- Shiels A, Bennett TM, Prince JB, Tychsen L. X-linked idiopathic infantile nystagmus
associated with a missense mutation in FRMD7. Mol Vis 2007; 13:2233-2241.
- Brantley MA, Fang AM, King JM, Tewari A, Kymes SM, Shiels A. Association of
Complement Factor H and LOC387715 genotypes with response of exudative AMD to
intravitreal bevacizumab. Ophthalmology 2007; 114:2168-2173.
- 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;
- Brantley MA, Edelstein SL, King JM, Plotzke M, Apte RS, Kymes SM, Shiels A.
Association of Complement Factor H and LOC387715 genotypes with response of
exudative age-related macular degeneration to photodynamic therapy. Eye (Lond)
- Lee AY, Raya AK, Kymes S, Shiels A, Brantley MA. Pharmacogenetics of
Complement Factor H (Y402H) and treatment of exudative age-related macular
degeneration with ranibizumab. Br J Ophthalmol (BJO) 2009; 93:610-613.
- Shi Y, Barton K, Petrash JM, Shiels A, Bassnett S. The stratified syncytium of the
vertebrate lens. J Cell Sci 2009; 122:1607-1615.
Invited Book Chapters
- Shiels A. Molecular genetics of cataracts. In: Pathobiology of Ocular Disease (3rd edn),
Klintworth and Garner eds, Marcel Dekker Inc., New York, 2008; Chapter 33, pp 713-
- Shiels A, Hejtmancik JF. Genetics of age-related cataract. In: Encyclopedia of the Eye,
Dartt, Besharse and Dana eds, Elsevier, 2010; Volume 2 D-L, pp 207-210.
- Shiels A, Hejtmancik JF. Genetics of congenital cataract. In: Encyclopedia of the Eye,
Dartt, Besharse and Dana eds, Elsevier, 2010; Volume 2 D-L, pp 211-216.