Patient ascertainment and collection of genetic material: A five-generation pedigree from Honduras with zonular pulveru-

Cataract, opacification of the crystalline lens of the eye, is the most common cause of blindness in the world [1]. The World Health Organization estimates that 45 million people in the world are blind, 19 million of them as a result of cataract [1]. Cataracts may be broadly divided into adult onset and childhood onset (either congenital or infantile). Congenital cataract is defined as cataract which is present from birth and is responsible for approximately one-tenth of worldwide childhood blindness [2]. The incidence of congenital cataract is between 2.2 and 2.49 per 10,000 live births [3,4]. About one third of isolated congenital cataracts are familial [5], the most common mode of inheritance being autosomal dominant [4,5]. Fourteen genes and at least six additional loci have been implicated in autosomal dominant congenital cataract (ADCC) [6]. The genes that have been identified comprise seven crystallins [7-18], three transcription factors [19-21], one cytoskeletal protein [22], and three transmembrane proteins [23-34]. The transmembrane proteins consist of connexin 46 (Cx46) [23,26-30,32], connexin 50 (Cx50) [24,31,33,34], and major intrinsic protein of the lens (MIP) [25]. Cx46 is a member of the connexin family of proteins. The connexins comprise proteins important for the formation of gap junction channels. Connexin proteins form hexamers known as connexons in cell membranes. Connexons in neighboring cells dock to form gap junctions which allow the transport of small metabolites between cells [35]. In humans, at least 20 connexin genes have been associated with several different diseases including genetic deafness, skin disease, peripheral neuropathies, heart defects and cataracts [36]. The lens expresses three distinct connexins, connexin 43 (Cx43), Cx46, and Cx50, all of which appear to have different functions in maintaining lens homeostasis [36]. The lens is an avascular structure and lens fibers lose all intracellular organelles during development. The lens has therefore developed an extensive intercellular communication system using gap junctions to maintain tissue homeostasis and hence transparency [37]. Cx43 is expressed mainly in the lens epithelial cells, while Cx46 and Cx50 are expressed in lens fiber cells [38-40]. Hence, mutations in Cx46 and Cx50 may lead to congenital cataracts. Pulverulent cataracts have a pulverized (powdery) appearance to opacification [41]. “Zonular pulverulent cataract” is a term which has been used to describe pulverulent cataracts which involve the nucleus minimally but markedly affect lamellar regions beyond it. AD zonular pulverulent cataracts have been described in association with mutations in GJA3 [30,32], GJA8 [24,31,33], and CRYGC [16] genes. A linkage approach was used to investigate the known cataract genes and loci in a large Hispanic pedigree from Honduras with zonular pulverulent cataract with the aim of identifying the causative mutation. A novel causative mutation in the connexin 46 gene (GJA3) was identified.