Characterization of Chromosomal Duplication Associated with Hereditary Benign Intraepithelial Dyskeratosis

Abstract

Abstract: : Purpose: Hereditary benign intraepithelial dyskeratosis (HBID) is an autosomal dominant cell proliferation disorder characterized by opaque epithelial plaques of the conjunctiva and oral mucosa. Found primarily among a Native American tribe in North Carolina and their relatives, HBID plaques appear at birth or in early childhood. Involvement typically includes the conjunctiva, cornea, and buccal mucosa. Loss of vision secondary to corneal involvement can occur. Recently, this disorder was linked to chromosome 4q35 and the presence of three microsatellite alleles in affected individuals revealed a near-telomeric DNA duplication in this region (Allingham RR, et al. Am J Hum Genet 2001). The proximal duplication endpoint was found to lie between markers D4S2299 and D4S2390 (227 kb). The purpose of this study was to further localize the proximal duplication endpoint. Methods: Tandyman (www.stdgen.lanl.gov/tandyman.index.html) was used to identify seven novel, potentially polymorphic microsatellite markers between D4S2299 and D4S2390. Analysis of a large HBID family (27 individuals, 16 affected, 7 non-affected, and 4 potentially affected) and a control population (48 individuals) was performed using these new markers. Results: Two markers located 30 kb and 64 kb proximal to D4S2390 resulted in duplicated alleles in all HBID affected individuals and in two potentially affected individuals. No duplicated alleles were observed in the control population for any of the seven markers analyzed. Conclusions: Based on these results the proximal duplication endpoint is located within a 46 kb region on 4q. Southern blotting will be performed to further localize the duplication endpoint. A cosmid-based genomic library is being constructed from patient DNA in order to clone and sequence the duplication endpoint.

Keywords: conjunctiva • gene mapping • genetics