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Two monogenic macular degenerations, the stargardt-like macular degeneration (STGD3) and the late-onset retinal dystrophy (L-ORD), are caused due to mutations in the genes elongation of very long chain fatty acid-4 (ELOVL4) and C1Q tumor necrosis factor-related protein-5 (CTRP5/C1QTNF5) genes, respectively. It has been shown that disease-causing mutations alter the trafficking of these proteins and exert dominant-negative effect. Selective elimination of these mutant proteins may facilitate restoring the normal function of retinal tissue. In this study, we describe characterization of small interfering RNA (siRNA) probes that selectively and effectively knock down the expression of the wild-type and mutant ELOVL4 and the wild-type CTRP5 genes in Cos-7 cells. These probes will be valuable in studying the function of wild-type ELOVL4 and CTRP5 genes, affect of mutant proteins and the potential use of gene silencing in treating STGD3 and L-ORD.

Blue cone monochromacy (BCM) is an X-linked ocular disorder in which affected males have normal short-wavelength-sensitive (blue) cone and rod function but lack medium-(green) and long-wavelength-sensitive (red) cone function. Affected males characteristically have visual acuities of 20/100 to 20/200, myopia, nystagmus, and minimal foveal granularity with otherwise normal fundus findings.1

We are studying a large autosomal dominant family with a broad clinical spectum of macular degeneration. By analyzing microsatellite markers on chromosome 6, significant positive lod sores were obtained (D6S455: Z = 4.49 at theta = 0). Linkage analysis localizes the disease-causing gene to a 22cM interval on chromosome 6q11–13 and excludes the loci for North Carolina Macular Dystrophy and Progressive Bifocal Chorioretinal Atrophy. Three other retinalJ.macular dystrophies map to overlapping intervals and could be allelic forms of the same gene or from a cluster of genes causing retinal/macular degeneration.

In recent years the field of retinal gene discovery has experienced an explosion. An estimated 10,000-30,000 genes are thought to be expressed in the human retina (Shimizu-Matsumoto et al., 1997), with nearly 5,000 retinal transcripts catalogued from expressed sequence tag (EST) datasets (Bortoluzzi et al., 2000) and over 26,000 different transcripts represented in retina serial analysis of gene expression (SAGE) libraries (Sharon et al, 2002). A wide variety of methods have been developed and utilized to define novel retinal genes, particularly in an effort to identify genes targeted in human retinopathies. To date there are 144 diseases of the retina described that have been mapped to human chromosomal locations, and an additional 41 human disorders involving some form of retinal dystrophy for which the genetic map locations have yet to be determined (RetNet Retinal Information Networkhttp://www.sph.uth.tmc.edu/retnet/;Online Mendelian Inheritance in Man (OMIM)http://www.ncbi.nlm.nih.gov/omim/). Despite recent efforts to discover novel genes by analyzing increasingly greater volumes of information arising from human genomic sequence data organization and expression studies, the disease genes for less than one-half of these conditions have at present been cloned. While some of these disorders may be attributed to allelic heterogeneity, a significant number of genes that account for retinal degenerative phenotypes remain to be defined.

We have analyzed 145 RS families for mutations in the XLRS1 gene and have sought clinical correlation of phenotype severity with the type and location of mutation in a subset of these families. Some of the RS families exhibited consistency of either severe or mild clinical phenotypes in multiple affected male members. Intrafamilial variability of clinical phenotypes was encountered in affected males of several other RS families.

The Usher Syndromes are a group of autosomal recessive disorders characterized by congenital sensorineural deafness and progressive pigementory retinopathy. Several types of Usher syndromes (Ush) have been distinguished by age of onset, rate of progression and severity of clinical symptoms.

Usher syndrome consists of a group of autosomal recessive diseases characterized by congenital sensorineural hearing loss and the progressively blinding disorder, retinitis pigmentosa. In 1914 Usher was the first to describe the hereditary nature of this syndrome (1). Usher syndrome is the most common cause of deaf-blindness, causing at least 50% of all reported cases of combined deafness and blindness in developed countries. Its prevalence in the general population ranges from 3 to 5 per 100,000 and estimates of gene frequency variy from 1/70 to 1/100 (2). The Diagnosis of Usher syndrome is generally made following ophthalmoscopic examination of congenitally deaf patients. In Usher syndrome patients patients retinitis pigmentosa is the most important ocular finding while sensorineural hearing loss is the most frequent non-ocular abnormality.