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  • The genes for four different inherited macular dystrophies were recently identified. These include Best vitelliform dystrophy, Doyne honeycomb retinal dystrophy (also known as malattia leventinese), Sorsby macular dystrophy, and Stargardt disease. The first three are autosomal dominant clinical disorders; Stargardt macular dystrophy is an autosomal recessive trait.

  • The gene for Best disease, VMD2, encodes bestrophin which is a tetraspan transmembrane protein of unknown function. Both the Doyne (EGF [epidermal growth factor]-containing fibrillin-like extracellular matrix protein 1 gene and protein (EFEMP1)) and Sorsby (TIMP-3) genes encode extracellular matrix proteins. The Stargardt macular dystrophy gene, ATP-binding cassette transporter retina-specific gene and protein (ABCR), encodes an ATP-binding cassette transporter that appears to transport retinaldehyde or a derivative across the rim of the photoreceptor disc membrane, possibly out of the rod outer segment disc to the cytosol of the rod photoreceptor. Each of the four genes is expressed in the retina; VMD2 is expressed specially in retinal pigment epithelium (RPE) and ABCR expressed exclusively in the photoreptor cells.

  • Mutations of VMD2, EFEMP1, and TIMP3 are associated with their respective macular dystrophies. However, homozygous and compound heterozygous mutations of ABCR are associated with a plethora of retinal phenotypes including: Fundus Flavimaculatus, Stargardt disease, combined cone-rod dystrophy, and retinitis pigmentosa (RP19). Some heterozygous ABCR mutations may be associated with a multifactorial disorder, Age-Related Maculopathy.


The human eye is an extraordinarily complex organ comprised of numerous tissues derived from all three embryologic layers. Thus, it is not surprising that the eye is a common site of manifestations of genetic disease, both single gene and multifactorial disorders. Indeed, a casual search through the major catalogs of hereditary disorders suggests that at least 25 percent of all human disorders either affect the eye primarily or involve ocular structures with distinctive or characteristic manifestations. The eye was the location for the first modern description of an hereditary disorder (colorblindness),1,2 the target of the first modern textbook of genetics,3 the source of the first mathematical modeling of an oncogene requiring two mutational events (retinoblastoma),4 the site of first isolation of a human oncogene (retinoblastoma),5 and the target of the first prenatal prediction of a cancer phenotype (retinoblastoma).6

Modern molecular technology has revolutionized the field of genetic eye research, beginning with the mapping of two different forms of X-linked retinitis pigmentosa in 1984 and 1985.7,8 The most common genetic eye diseases encountered clinically, and those that have been studied most extensively, are disorders of the retina and RPE, caused by defects in the structure or function of the photoreceptors or the RPE itself. For simplicity, retinal dystrophies have been classified into two types, those that primarily or initially affect the peripheral vision, such as retinitis pigmentosa (RP), and those that primarily affect central vision, the macular area. (In this chapter, the macular area means the zone of ...

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