Clinical and genetic features of TGFBI-linked corneal dystrophies in Mexican population: Description of novel mutations and novel genotype–phenotype correlations Juan Carlos Zenteno a, b, * , Vicente Correa-Gomez b , Concepcio ´ n Santacruz-Valdez c , Raul Suarez-Sanchez c , Cristina Villanueva-Mendoza d a Department of Biochemistry, Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico b Department of Genetics-Research Unit, Institute of Ophthalmology ‘‘Conde de Valenciana’’, Chimalpopoca 14, Col. Obrera, Mexico City 06800, Mexico c Department of Cornea, Institute of Ophthalmology ‘‘Conde de Valenciana’’, Chimalpopoca 14, Col. Obrera, Mexico City 06800, Mexico d Department of Genetics, ‘‘Dr. Luis Sa ´nchez Bulnes’’ Hospital and the ‘‘Asociacio ´n para Evitar la Ceguera en Me´xico’’, Mexico City, Mexico article info Article history: Received 3 October 2007 Accepted in revised form 11 March 2009 Available online 18 March 2009 Keywords: corneal dystrophies TGFBI gene TGFBI mutation corneal disease abstract Corneal dystrophies (CDS) are inherited disorders characterized by an altered corneal transparency and refractive index which may be caused by a progressive accumulation of deposits within the different corneal layers. Most CDs are inherited in an autosomal dominant fashion and mutations in the TGFBI gene at chromosome 5q31 cause the majority of CDs affecting the stromal layer. A genotype–phenotype correlation has been identified in most analyzed populations as specific amino acid changes in TGFBI protein cause specific stromal phenotypes. However, analysis of additional populations will help to broaden the mutational spectrum ultimately allowing a better clinical–molecular classification of patients with this group of diseases. In this work, eighteen unrelated Mexican probands suffering from stromal CDs were clinically assessed and their TGFBI gene status investigated. Complete ophthalmologic evaluation, including biomicroscopic inspection and dilated fundus examination, was performed. In addition, detailed genealogical analyses as well as automated DNA sequencing of the entire TGFBI gene were done in all probands. Mutation-carrying exons were examined in 50 first and second degree relatives. Phenotypic analysis disclosed the occurrence of 6 cases of lattice CD, 6 of granular CD, 2 of granular type 2 (Avellino CD), 2 of polymorphic corneal amyloidosis, 1 of Reis–Bucklers CD, and 1 of an unclassifiable phenotype. TGFBI mutations were identified in all 18 probands. A total of six different mutations were observed: p.V113I, p.M502V, p.A546D, p.L550P, p.R555W, and p.H626R. Of these, mutations p.L550P (originated by the change c.1649T>C at exon 12), p.M502V (c.1504A>G, at exon 11), and p.V113I (c.337G>A, at exon 4), are novel TGFBI mutations. All subjects with lattice CD in our sample carried the p.H626R mutation. No instances of defects at codon 124, one of the two most frequently mutated sites in TGFBI-linked CDs, were detected. A distinct TGFBI mutational pattern was identified in Mexican patients with stromal CDs. Novel TGFBI mutations and new genotype–phenotype correlations were also recognized. This study stresses the importance of performing TGFBI genetic analysis in distinct CD populations. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction Corneal dystrophies (CDs) are genetically determined diseases in which the progressive opacification of corneal layers results in variable loss of its transparency and eventually in visual impair- ment (Chang et al., 1998). CDs are most often bilateral diseases that initiate during the two first decades of life and exhibit a substantial intra- and interfamilial variation in clinical expressivity (Rodrigues and Krachmer, 1988; Klintworth, 1999; Weiss et al., 2008). Affected individuals experience diminished corneal sensitivity, foreign body sensation (if corneal erosions occur), halos around lights, and progressive visual impairment between the 3rd to the 5th decades of life. The majority of CDs recognized to date are transmitted * Corresponding author. Department of Genetics, Institute of Ophthalmology ‘‘Conde de Valenciana’’, Chimalpopoca 14, Col. Obrera, Mexico City 06800, Mexico. Tel.: þ5255 54421700x3212; fax: þ5255 54421700x3414. E-mail address: jczenteno@institutodeoftalmologia.org (J.C. Zenteno). Contents lists available at ScienceDirect Experimental Eye Research journal homepage: www.elsevier.com/locate/yexer 0014-4835/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.exer.2009.03.004 Experimental Eye Research 89 (2009) 172–177