Clinical Review of Genetic Eye Disease

1. Clinical Review of Genetic Eye Disease Optometry 8570 Fall 2008

2. Recall… • Cell function in all human tissues depends on the activities of specific protein molecules • Protein activity is dependent upon gene expression that contains the correct DNA sequence for exact protein synthesis • Should know: • Process of gene expression (“Central Dogma”) • Mitosis and meiosis • Basic Mendelian principles

3. Mutation • Changes in the gene DNA sequence that result in a biologically significant change in the function of the encoded protein • Protein product might not be made at all • Protein product might be produced but work poorly • Protein product may have an adverse effect on the cell (“dominant negative effect”) • Point mutations (substitution of a single base pair) are the most common mutation in humans • Missense mutations are point mutations that cause a change in the amino acid sequence of the polypeptide chain

4. Mutation • Chromosal rearrangement often results in breaks in specific genes, causing interruption in the normal DNA sequence • Usually results in truncated, unstable dysfunctional protein product • Occasionally the broken gene fuses with another gene to cause a “fusion polypeptide product” which may have novel activity (which may result in functional abnormality) • Example: Many leukemias caused by a fusion protein product caused by translocation of chromosome 9;22

5. Inheritance Patterns • Understand and Review: • Autosomal dominant • Autosomal recessive • X-linked • Mitochondrial

6. Resources to Investigate • National Center for Biotechnology Information: http://www.ncbi.nlm.nih.gov/sites/entrez?db=OMIM • Online Mendelian Inheritance in Man: http://www.ncbi.nlm.nih.gov/sites/entrez?db=OMIM • Expression Databases: http://neibank.nei.nih.gov • RetNet (Retinal disease genes): www.sph.uth.tmc.edu/RetNet/

7. Resources to Investigate • LENSNET (Lens disease genes): www.ken.mitton.com/ern/lensbase.html • GENES and DISEASE (Systemic inherited disorders): www.ncbi.nlm.nih.gov • Center for Medical Genetics (Gene and genetic marker maps): http://research.marshfieldclinic.org/genetics • UCSC (Human Genome Sequence): http://genome.ucsc.edu

8. Chromosomal Locations of Disease Genes with Ocular Manifestations

9. Butterfly-shaped pattern dystrophy 6p Cataract, Coppock-like 2q33 - q35 Cataract, posterior, polar 16 Cataract, pulverulent, zonular, Coppock type 1q21 - q25 Cataract, zonular, Mariner type 16 Cataract, anterior, polar 12p25 or 14q24 Cataract, anterior, polar 2p26.2 or 4p15 Cataract, congenital, total Xp Cerebrotendinous xanthomatosis 2q33-qter2,3 CHARGE association 6cen/8cen2,3 Choroideremia Xq21.2 Coats' syndrome 3p21 or 3q28 Cokayne's syndrome 2q21 Collagen, type II, alpha-1 chain (Stickler's syndrome) 12q13.1 - q13.3 Collagen 1, alpha-1 chain (Marfan's syndrome) 17q21.3 - q22.05 Coloboma of iris 2pter - p25.1 Color blindness, blue-cone monochromasy Xq28 Color blindness, deutan (green-cone pigment) Xq28 Color blindness, protan (red-cone pigment) Xq28 Cone dystrophy 1 Xp21.1 - p11.3 Cone dystrophy 2/defect of red-cone pigment Xq28 Cone dystrophy 3q27 Cone-rod dystrophy 18q21.1 - 22.2 Cone pigment, blue 7 Congenital stationary night blindness Xp11.3 Craniosynostosis 7p21.3 - 21.2 Dyslexia 1 15q11 Fabry's disease Xq22 Familial exudative vitreoretinopathy 11q13.5 - q22 Focal dermal hypoplasia (Goltz's syndrome) Xp22.31

10. Galactosemia 1 9p13 Glaucoma, juvenile open-angle 1q21 - q31 GM1 gangliosidosis 3p21-cen GM2 gangliosidosis, AB variant 5 Goldenhar syndrome (conjunctival dermoids) 7p21.3 - 21.2 Green/blue eye color 19 Gyrate atrophy 10q26 Homocystinuria 21q22.3 Hurler-Scheie syndrome 2q11 Incontinentia pigmenti Xq27 - 28 Iris coloboma 2pter - 2p25.1 Kearns - Sayre syndrome mtDNA Krabbe's disease (galactocerebrosidase) 17 Leber's hereditary optic neuropathy Xp1 Leber's hereditary optic neuropathy mtDNA Lowe's oculocerebrorenal syndrome Xq25 Macular dystrophy, atypical vitelliform 8q24 Macular dystrophy, vitelliform, Best's type 11q13 Marfan's syndrome, type I alpha 2 17q21.3 - q22.05 Marfan's syndrome 1 15q15 - q21.3 Maroteaux-Lamy syndrome (mucopolysaccharidosis VI) 5q11 - q13 Megalocornea, X-linked Xq12 - q26 Microphthalmia Xp22 Möbius's syndrome 13q2 Morquio's syndrome B (mucopolysaccharidosis IVB) 3p21 - cen Multiple endocrine neoplasia II (IIA) 10q21.1 Multiple endocrine neoplasia III (IIB) 10q21.1 Myopia 1, X-linked, Bornholm eye disease Xq28

11. Myotonic dystrophy 19q13.1 Nance-Horan syndrome Xp22.3 - p21.1 Neurofibromatosis 1 17q11.2 Neurofibromatosis 2 (acoustic neuroma) 22q11 - q12.2 Nevoid basal cell carcinoma syndrome 1p Niemann-Pick disease (sphingomyelinase) 17 Niemann-Pick, type Al sphingomyelinase) 11p15.4 - p15.1 Norrie's disease Xp11.4 - p11.3 North Carolina macular dystrophy 6q16 Ocular albinism (Nettleship-Falls type) Xp22 Optic atrophy 18 Optic atrophy (Kjer type) 2p Optic atrophy, polyneuropathy and deafness Xqdistal Pelizaeus-Merzbacher Xq21.3 - q22 Peripherin-retinal degeneration 6p Phenylketonuria 12q22 - q24.1 Retinitis pigmentosa 1 8p11 - q21 Retinitis pigmentosa 2 Xp11.4 - p11.23 Retinitis pigmentosa 3 Xp21.1 Retinitis pigmentosa 4 (rhodopsin) 3q21 - q23 Retinitis pigmentosa 6 Xp21.3 - 21.2 Retinitis pigmentosa 7 (RDS, peripherin/RDS) 6p21.1 - cen Retinitis pigmentosa 8 19q13 Retinitis pigmentosa 9 7p15 - 13 Retinitis pigmentosa 10 7q Retinitis pigmentosa (Rod cGMP phosphodiesterase) 4p16.3 Retinitis pigmentosa (ROM1, digenic with peripherin/RDS) 11p13 Retinitis pigmentosa (rd, RP-cGMP channel protein-1) 4p14

12. Retinoblastoma 13q14.1 - q14.2 Retinoschisis Xp22.3 - p22.1 Rieger's syndrome 4q22.2 - q25 Rod GMP phosphodiesterase 4p16 Rod outer segment protein 1 11p13 S-antigen 2q24 - q37 Sandhoff's disease 5q13 Sanfilippo's syndrome 12q14 Stargardt's 1 disease (autosomal-dominant) 13q34 Stargardt's 2 disease (autosomal-dominant) 6q Stargardt's 3 disease (autosomal-recessive) 1p Stickler's syndrome 12q13.1 - 13.3 Tapetochoroidal dystrophy Xq21.1 - q21.2 Tay-Sachs disease 15q22 - q25.1 Tritanopia 7q22 - qter Tuberous sclerosis 1 9q34 Tuberous sclerosis 2 11q22 - q23 Tuberous sclerosis 3 12q22 - q24.1 Usher's syndrome, 1 14q Usher's syndrome, 2 1q Vitelliform dystrophy 8q von Hippel-Lindau disease 3p25 - p24 Waardenburg's syndrome 2q35 Werner's syndrome 8 Wieaclcer-Wolff Xq11 - q12 Wilson's disease 13q14 - q21 Wolf-Hirshhorn syndrome 4pter - p16.3 Zellweger's syndrome 7q11.12 - q11.23

13. Know the basics… • For the more common hereditary disorders: • What are the most common presenting clinical symptoms and signs? • Where is the protein defect thought to exist? • What change in physiology is caused by the protein defect?

14. Clinical Example-Dominant Corneal Dystrophies • Excellent examples of autosomal dominant corneal mutations that result in a toxic protein • 4 have been described that affect the anterior corneal stroma: • Groenouw’s (granular) type I • Lattice type 1 • Avellino (combined granular-lattice) • Reis-Buckler’s

15. Clinical Example-Dominant Corneal Dystrophies • All 4 have been mapped to a common interval on chromosome 5q31 • Mutations in the gene big-h3 located in this region have been identified in affected familes • This gene product is keratoepithelin, probably an extracellullar matrix protein modulating cell adhesion • At least four different missense mutations, which occur at the arginine codons in the gene, have been found so far

16. Clinical Example-Stargardt’s Disease • Characterized by progressive bilateral atrophy of the macular RPE and neuroepithelium, with frequent appearance of orange-yellow flecks around the macula; the choroid is characteristically dark on FA • Loss of acuity may have juvenile to adult onset; condition is autosomal dominant • Mutation in a photoreceptor cell-specific ATP-binding transporter gene (ABCR) is responsible

17. Clinical Example-Stargardt’s Disease • Most mutations so far reported are missense mutations in conserved amino acid positions • The retina-specific ABC transporter responsible for Stargardt’s is a member of a family of transporter proteins expressed in rod photoreceptors • Indicates that this protein mediates the transport of an essential molecule either into or out of photoreceptor cells • This likely results in the accumulation of a lipofuscin-like substance due to inactivation of this transporter protein