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  • Review Article
  • Published:

The genetic and molecular basis of congenital eye defects

Nature Reviews Genetics volume 4, pages 876–888 (2003)Cite this article

Key Points

  • Mutations that lead to clinically relevant eye phenotypes (such as anophthalmia, microphthalmia, aniridia, coloboma and cataract) highlight important steps in the development of this organ.

  • This information allows us to establish a genetic hierarchy in which genes such as PAX6, SIX3 and SOX2 lie at the top, other genes (such as FOXC1, FOXE3, PITX3 and MAF) function downstream and tissue-specific genes such as the crystallin-encoding genes are the final targets.

  • The ongoing and rapidly increasing characterization of mutations in humans and mice indicates that the frequency of mutations that lead to eye defects is not randomly distributed among the genes that are involved in eye development: some genes (including PAX6, PAX2 and CRYG) are frequently affected by mutations, whereas others are not targeted either by spontaneous or experimentally induced mutations in the mouse.

  • Allelic series of mutations show that similar clinical phenotypes might be caused by mutations in different genes; by contrast, mutations in the same gene do not necessarily lead to the same phenotype, which indicates the importance of as yet unknown modulators of gene expression or function.

  • The detailed molecular analysis of allelic series of mutations will also allow detailed genotype–phenotype correlations to be made, which should uncover the function of particular domains of the mutated proteins.

Abstract

The mature eye is a complex organ that develops through a highly organized process during embryogenesis. Alterations in its genetic programming can lead to severe disorders that become apparent at birth or shortly afterwards; for example, one-half of the cases of blindness in children have a genetic cause. This review outlines the genetic basis of eye development, as determined by mutation analysis in patients and in model organisms. A better understanding of how this intricate organ develops at the genetic and cellular level is central to our understanding of the pathologies that afflict it.

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Figure 1: Schematic section through an adult human eye.
Figure 2: Schematic view of a developing vertebrate eye.
Figure 3: Histological sections through a developing mouse eye.
Figure 4: The CRYG gene cluster.

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Acknowledgements

I would like to thank the many friends and colleagues who have supported my work in the past years. In particular, I am grateful to V. van Heyningen (Edinburgh), who contributed many ideas and detailed comments to this review in its initial phase. Unfortunately, owing to space limitations, I could not refer to all papers on the molecular aspects of eye development, and I apologize to colleagues whose work has not been cited.

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    Jochen Graw

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microphthalmia

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FURTHER INFORMATION

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Human Genomic Sequence Database

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Mouse Genomic Sequence Database

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Glossary

CATARACT

Opacity of the entire lens or its parts.

COLOBOMA

Incomplete closure of the fissure of the embryonic optic cup, which mainly affects the iris.

EYE FIELD

A central region in the anterior neural plate that gives rise to the eyes by bilateral expansion.

CORNEA

The transparent convex portion of the anterior eye

LENS

The transparent biconvex part of the eye between the iris and the vitreous humour, which focuses light rays on the retina. The shape of the lens is in part determined by the pull or lack of pull of the ciliary body.

IRIS

The disc-shaped pigmented contractile membrane of the eye that is attached at its margin to the ciliary body and is perforated centrally by the pupil.

CILIARY BODY

The part of the eye between the choroid and the iris to which the ciliary muscle is attached.

VITREOUS HUMOUR

A jelly-like substance that fills the eyeball behind the lens and is a support for the structure of the eye. It also maintains the transparency of the eye, as it is impervious to debris.

RETINA

The light-sensitive membrane of the posterior eye onto which the light is focused by the lens and which contains the sensory cells (rods and cones) that allow vision.

CHOROIDEA

The choroid (choroidea) lies between the retina and the sclera. It is composed of layers of blood vessels that nourish the back of the eye.

GLIAL CELL

These cells outnumber neurons by about five to one in the nervous system, they have processes but do not form or conduct action potentials; they retain the capacity to divide throughout life and several subtypes are known.

GANGLION

A general term that is used to refer to a nerve or neuronal cell.

ENDOTHELIUM

The layer of cells that lines the heart, blood vessels and other body cavities.

KERATINOCYTE

A particular cell type in the cornea that is defined by the expression of keratins.

MESENCHYME

Embryonic connective tissue that is composed of star-shaped cells in an extracellular matrix.

PHOTOTRAINMENT

The process whereby light exposure synchronizes the endogenous circadian pacemaker, which causes the molecular cycles of clock protein transcription, dimerization and translocation to begin again before completing an entire cycle.

OPTIC CUP

A cup-like depression in the optic vesicle, which develops into the sensory (neural) and pigmented layers of the retina.

OPTIC VESICLE

Paired protrusions of the embryonic forebrain from which the pigmented and sensory layers of the retina derive.

PLACODE

A thickening of the surface ectoderm in the head region of the early vertebrate embryo that gives rise to the future sensory organs (eye, nose and ear). The lens placode develops into the prospective lens.

LENS FIBRES

Inner cells of the lens, which are organized as long connected fibres that span from the posterior to the anterior pole; this arrangement allows accommodation and transparency, together with high mechanic stability.

LENS SUTURES

The connection of the secondary lens fibre cells at the anterior or posterior pole of the lens.

ECTODERM

The outer most of the three primary germ layers of the embryo, from which the skin, nerve tissue and sensory organs develop.

NEURAL CREST CELLS

A band of neuroectodermal cells located dorsal and lateral to the neural plate in the embryo. These cells migrate to their final destinations and develop into the corresponding derivatives. In the cornea, these cells form the stroma.

STROMA

The connective tissue or supporting framework of an organ (in this case, the cornea).

ACCOMMODATION

A function of the lens in which it adjusts to keep near and distant objects in focus on the retina.

OPTIC STALK

This begins as a narrow channel that connects the optic cup and the brain, but as development progresses it is invaded by neuronal processes that emanate from the ganglion cells of the retina.

OMMATIDAL EYES

The complex eyes of insects that are composed of many single eye units or ommatidia (for example, there are 750–800 in each Drosophila eye).

ANIRIDIA

Partial or complete loss of the iris.

MACULAR HYPOPLASIA

In this condition, the fovea, which is a tiny area in the centre of the macula region of the retina that is the most sensitive area of vision, fails to fully develop.

KERATITIS

An inflammation or irritation of the cornea, which is often characterized by cloudiness or loss of lustre. There are many types, causes and degrees of severity. Generally, the infection occurs after the cornea has been injured or penetrated, allowing bacteria or fungi to enter.

PETERS ANOMALY

Central cornea opacity, which is frequently associated with adhesion between the cornea and the lens.

HOLOPROSENCEPHALY

A set of developmental anomalies that are associated with impaired midline cleavage of the embryonic forebrain, the absence of the olfactory bulbs and tracts, and midline dysplasia of the face, which is frequently associated with cleft lip and palate.

HAPLOINSUFFICIENCY

A gene dosage effect that occurs when a diploid requires both functional copies of a gene for a wild-type phenotype. An organism that is heterozygous for a haploinsufficient locus does not have a wild-type phenotype.

ANLAGE

(Plural anlagen). A simple preliminary organ structure in the embryo.

PENETRANCE

The proportion of individuals with a specific genotype that manifest this genotype at the phenotype level.

CYCLOPIA

The presence of a single central eye field, which results in a slit for an eye (although no actual eye is present); the name is based on Homer's description of the mythical 'cyclops'.

RIEGER ANOMALY

Axenfeld syndrome (a white ring at the back of the cornea associated with iris processes and glaucoma) that is associated with contact between the iris and the cornea; Rieger syndrome is also associated with anomalies of the skeleton and teeth.

IRIDOGONIODYSGENESIS

A syndrome that includes glaucoma and dysgenesis of the iris and the gonads.

GLAUCOMA

Degeneration of the optic nerve; the principal symptom is increased ocular pressure.

PULVERULENT CATARACT

Powder-like cataract (lens opacity).

GAP JUNCTION

A type of junction between two cells through which ions and small molecules can pass.

GENE CONVERSION

A meiotic process of directed change in which one allele directs the conversion of a partner allele to its own form.

SLIPPAGE

A mutagenic process during DNA replication: the presence of several identical base pairs in a series might cause the DNA polymerase to add or omit one by sliding over the template.

WAARDENBURG SYNDROME TYPE 2

A syndrome that consists mainly of deafness, partial albinism and anomalies in fundus pigmentation and iris colour.

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Graw, J. The genetic and molecular basis of congenital eye defects. Nat Rev Genet 4, 876–888 (2003). https://doi.org/10.1038/nrg1202

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