Shiels Lab

Alan Shiels PhD, Professor, Ophthalmology and Visual Sciences, Department of Genetics

 Dr. Shiels’ profile

Research

Our research focuses on the molecular genetic mechanisms underlying pediatric and age-related forms of cataract(s) – a clinically important cause of visual impairment (low vision and blindness). Genome-wide mapping and targeted sequencing techniques are combined to 1) define chromosomal loci for inherited cataract, 2) identify causative mutations for inherited cataract or susceptibility variants for age-related cataract, 3) facilitate precise genetic testing for cataract, and 4) enhance genetic counseling for cataract running in families. Currently, functional expression studies in several gene-targeted/edited mice are being used to model the underlying patho-genetic mechanisms leading to lens dysgenesis and cataract. Results from these studies will advance understanding of lens and anterior eye development in health versus disease and contribute toward the design of gene-based therapeutics that may help treat or prevent common causes of visual impairment.

Molecular Genetics of Cataract and Associated Eye Disorders

 

The crystalline lens plays a central role in vertebrate eye development and refractive vision. Loss of eye lens transparency or cataract(s) is a clinically heterogeneous disorder that despite surgical treatment remains an important cause of visual impairment worldwide. Typically, cataract is acquired with aging (> 40 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 an early onset (birth – 40 years) in either the absence or presence of other ocular and/or systemic abnormalities. Click on the Cat-Map link to view a comprehensive genetic map of cataract. Research in our laboratory aims to unravel molecular genetic mechanisms underlying inherited and age-related forms of cataract using two complementary approaches:

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.
  2. 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. Genetic determinants of autosomal dominant cataract discovered in the Shiels lab.

Chromosome (co-ordinates)

Gene

Exon

DNA Change

Protein Change

Cataract Phenotype

1 (16124337-16156109, complement)

EPHA2

17

c.2842G>T

p.G948W

Posterior polar

1 (147902820-147915287)

GJA8

2

2

c.142G>A

c.262C>T

p.E48K

p.P88S

Zonular nuclear pulverulent

Zonular pulverulent

2 (208121607-208124589, complement)

CRYGD

2

c.70C>A

p.P24T

Coral-like

9 (70529063-71446950, complement)

TRPM3

3

c.195A>G

p.I65M

Polymorphic (± glaucoma)

13 (20138252-20161327, complement)

GJA3

2

2

2

c.176C>T

c.188A>G

c.1137insC

p.P59L

p.N63S

p.S380fsX87

Nuclear punctate

Variable pulverulent

Punctate

20 (33811304-33854367)

CHMP4B

3

3

c.386A>T

c.481G>A

p.D129V

p.E161K

Posterior sub-capsular

Posterior polar

21 (43169008-43172810)

CRYAA

1

c.145C>T

p.R49C

Central nuclear

22 (26599278-26618104, complement)

CRYBB1

6

c.728G>T

p.G220X

Central sutural pulverulent

  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 cataract mutants characterized in the Shiels lab.

Chromosome

(co-ordinates)

Gene

 

Mutant allele

Exon/

Intron

DNA change

Protein change

Lens Phenotype

4 (141301221-141329384)

Epha2

tm1Jrui (neo)

Ex-5

null

null

Refractive defects, lens cell patterning defects

7 (43430101-43435991)

Lim2

Gt(VICTR48)Lex

IVS-3

null

null

Refractive defects and pulverulent opacities

10 (128225810-128231812)

Mip/Aqp0

Catlop

Ex-1

c.151G>C

p.A51P

Dense central opacity, microphakia

Gt(VICTR20)8Lex

Ex-1

null

null

Polymorphic opacities

CatFr

IVS-3

c.607-789delLTR

p.203-263delLTRX59

Shrivelled, microphakia

CATMAP

 

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.

http://cat-map.wustl.edu/

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

Publications

View all Alan Shiels NCBI publications on PubMed»

 

Recent Peer-reviewed Papers

 

Recent Book Chapters

  • Shiels A, Cabrera PE, Hejtmancik, JF. Genetics of age-related cataract. In: Reference Module in Neuroscience and Biobehavioral Psychology, Elsevier, 2017 
  • Shiels A, Hejtmancik JF. Chapter Twelve – Molecular Genetics of Cataract. In: Hejtmancik JF, John MN, editors. Progress in Molecular Biology and Translational Science. Volume 134: Academic Press; 2015. p. 203-218.
  • Shiels A, Hejtmancik JF. Age-related cataract. In: Clinical Genomics – Practical Application in Adult Patient Care, 1e (eds) Murray MF, Babyatsky MW, and Giovanni MA, McGraw-Hill Companies, Inc., 2014:725-730.