New mutations identified in the ocular albinism type 1 gene Cristin Roma a,1 , Paola Ferrante a,b,1 , Ombretta Guardiola a,b , Andrea Ballabio b,d , Massimo Zollo a,b,c, ⁎ a CEINGE-Biotecnologie Avanzate, Naples, Italy b Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy c Dipartimento di Biochimica e Biotecnologie Mediche, Università degli Studi di Napoli, Federico II, Naples, Italy d Medical Genetics, Department of Pediatrics, Federico II University, Naples, Italy Received 24 March 2007; received in revised form 5 July 2007; accepted 10 July 2007 Received by D.A. Tagle Abstract As the most common form of ocular albinism, ocular albinism type I (OA1) is an X-linked disorder that has an estimated prevalence of about 1:50,000. We searched for mutations through the human genome sequence draft by direct sequencing on eighteen patients with OA1, both within the coding region and in a thousand base pairs upstream of its start site. Here, we have identified eight new mutations located in the coding region of the gene. Two independent mutations, both located in the most carboxyterminal protein regions, were further characterized by immuno- fluorescence confocal microscopy, thus showing an impairment in their subcellular distribution into the lysosomal compartment of Cos-7A cells. The mutations found can result in protein misfolding, thus underlining the importance of the structure-function relationships of the protein as a major pathogenic mechanism in ocular albinism. Seven individuals out of eighteen (38.9%) with a clinical diagnosis of ocular albinism showed mutations, thus underlining the discrepancies between the clinical phenotype features and their genotype correlations. We postulate that mutations that have not yet been identified are potentially located in non-coding conserved regions or regulatory sequences of the OA1 gene. © 2007 Elsevier B.V. All rights reserved. Keywords: GPR143 (OA1); Sequence; Analyses; Mutation 1. Introduction Ocular albinism type I (ocular albinism of the Nettleship-Falls type; MIM 300500) is an X-linked disorder and it is the most common form of ocular albinism, with an estimated prevalence of about 1:50,000 (King et al., 1995). Phenotype analyses show that it is seen first as an isolated albinism of the eye, while skin pigmentation remains normal. The disease typically results in severely impaired visual acuity. Affected males manifest a depigmented fundus, translucent iris, strabismus, nystagmus, photophobia and misrouting of the optic pathway. Ultramicro- scopic analyses of melanocytes from affected patients demon- strates a variable portion of abnormally giant melanosomes, “macromelanosomes” (O'Donnell et al., 1976; Creel et al., 1978; Garner and Jay, 1980). This phenomenon is the prevalent clinical feature, associated with a decreased visual acuity that can cause severe visual handicap, due to foveal hypoplasia. In addition, these patients show misrouting of the optic tracts, which results in a loss of stereoscopic vision from the non-symmetric patterns of the visual evoked potentials (King et al., 1995). In carrier females, the fundus shows a spotty pigmentation. The mosaic pattern suggests that the gene is subject to X-inactivation. The OA1 gene (GPR143, [GenBank NM 000273]) is expressed in skin and retinal pigmented epithelium (RPE) cells. In these cells, the melanosomes are larger than normal melanosomes (O'Don- nell et al., 1976; Garner and Jay, 1980). The OA1 gene spans about 40 kb of genomic DNA in chromosome Xp22.3 and it is organized into nine exons (Schiaffino et al., 1995; Bassi et al., Gene xx (2007) xxx – xxx + MODEL GENE-35961; No of Pages 8 www.elsevier.com/locate/gene Abbreviations: bp, base pair(s); GPCR, G-protein-coupled receptor; pBS (SK-), pBluescript II SK-. ⁎ Corresponding author. CEINGE, Biotecnologie Avanzate SCARL, Via Comunale Margherita 482, 80145 Napoli, Italy. Tel.: +39 081 3737875; fax: +39 081 3722711. E-mail address: zollo@ceinge.unina.it (M. Zollo). 1 These two authors contributed equally to the work. 0378-1119/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.gene.2007.07.020 ARTICLE IN PRESS Please cite this article as: Roma, C. et al. New mutations identified in the ocular albinism type 1 gene. Gene (2007), doi:10.1016/j.gene.2007.07.020