An ENU-induced mutation in Rs1h causes disruption of retinal structure and function.

X-linked retinoschisis (XLRS), the leading cause of ju-venile macular degeneration affecting males, is caused bymutations in the RS1 gene [1]. While hemizygous affectedmales present with microcystic-like changes of the macula andschisis of inner retinal layers, peripheral lesions also are presentin about 50% of cases [2-5]. Visual impairment is typicallymanifest by age 5 in boys. The progression of the disease isslow and complications such as vitreal hemorrhage, choroidalsclerosis, and retinal detachment can occur later in life. Fe-male obligate carriers are typically asymptomatic with no clini-cal features, although Kaplan et al. [6] found that heterozy-gous females can have full expression of the retinal disease.The expression of XLRS is variable even within families.Moreover, the severity of disease expression is not mutationspecific [7].The human RS1 gene consists of six exons that encodefor a 224 amino acid protein of 24 kDa. The Rs1 protein issoluble, secretory, and forms disulfide-linked dimers andoctamers [8]. The predicted protein sequence contains threedomains: a signal sequence encoded by exons 1 and 2 (aminoacids 1-23); an Rs1 domain encoded by exon 3 (amino acids23-62); and a discoidin domain encoded by exons 4-6 (aminoacids 63-219). In addition, there is a five amino acid segmentpresent on the C-terminal side of the discoidin domain [9]. Todate, over 133 different mutations in RS1 have been docu-mented [8] (see the RetinoschisisDB for details on specificmutations provided by the Retinoschisis Consortium). Mosthuman mutations are in the discoidin domain with relativelyfew in signal or Rs1 domains, thereby suggesting that thediscoidin domain and its putative role in cell adhesion are criti-cal to the function of the protein [10-12].Although the precise function of the protein remains in-completely understood, recent studies have determined thatwild-type retinoschisin plays a role in both retinal cell adhe-sion [9,13,14] and synaptic integrity between photoreceptors