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VSX1 Mutational Analysis in a Series of Italian Patients Affected by Keratoconus: Detection of a Novel Mutation

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VSX1 Mutational Analysis in a Series of Italian Patients Affected by Keratoconus: Detection of a Novel Mutation VSX1 Mutational Analysis in a Series of Italian Patients Affected by Keratoconus: Detection of a Novel Mutation Luigi Bisceglia,1 Marilena Ciaschetti,2 Patrizia De Bonis,1 Pablo Alberto Perafan Campo,2 Costantina Pizzicoli,3 Costanza Scala,1 Michele Grifa,1 Pio Ciavarella,1 Nicola Delle Noci,3 Filippo Vaira,4 Claudio Macaluso,5 and Leopoldo Zelante1 PURPOSE. Keratoconus is a noninflammatory corneal disorder Most cases of keratoconus appear to be sporadic, but a that is clinically and genetically heterogeneous. Mutations in positive family history has been documented in 6% to 10% of the VSX1 (visual system homeobox 1) gene have been identi- patients.5 Both recessive and dominant patterns of inheritance fied for two distinct, inherited corneal dystrophies: posterior have been described.6–8 Autosomal dominant inheritance has polymorphous corneal dystrophy and keratoconus. To evalu- more frequently been reported in families, showing incom- ate the possible role of the VSX1 gene in a series of Italian plete penetrance and variable expressivity. Subtle videokerato- patients, 80 keratoconus-affected subjects were screened for graphic anomalies have been reported among relatives of pa- mutations. tients with keratoconus, allowing the detection of low- ETHODS expressivity forms of keratoconus, usually referred to as M . The diagnosis of keratoconus was made on the basis 9–11 of clinical examination and corneal topography. The whole subclinical or forme fruste keratoconus. Multifactorial in- heritance and a major gene model have also been pro- coding region and the exon–intron junctions of the VSX1 gene 12,13 were analyzed by direct sequencing. posed. In some cases nongenetic causes have been postu- lated, such as eye rubbing or rigid contact lens wear, which RESULTS. Three already-described changes, D144E, G160D, and could be responsible for keratoconus phenocopies. However, P247R, and a novel L17P mutation were found in 7 of 80 in these cases, mechanical trauma may behave only as a pre- unrelated patients (8.7%). Two undescribed intronic polymor- cipitating factor.14 Two candidate genes, COL6A1, located on phisms are also reported. the telomeric region of chromosome 21, and matrix metallo- CONCLUSIONS. Mutational analysis of the VSX1 gene in a series of proteinase-9 (MMP9), located at 20q11.2-q13.1, were excluded Italian patients revealed one novel mutation and confirmed an as causative genes by two different studies.15,16 A locus for important role played by this gene in a significant proportion autosomal dominant keratoconus was mapped on 16q22.3- of patients affected by keratoconus, when it is inherited as an q23.1 by Tyynismaa et al.17 in Finnish families. Recently, two autosomal dominant trait with variable expressivity and incom- further loci for autosomal dominant keratoconus have been plete penetrance. (Invest Ophthalmol Vis Sci. 2005;46:39–45) reported: one associated with cataracts on the long arm of DOI:10.1167/iovs.04-0533 chromosome 15 and one at p14-q13 on chromosome 3.18,19 Mutations in the VSX1 gene have been found in Canadian eratoconus (Mendelian Inheritance in Man [MIM] 148300) patients affected by either keratoconus or posterior polymor- Kis a frequent corneal dystrophy characterized by progres- phous corneal dystrophy (PPCD) by He´onetal.20 sive conical protrusion of the cornea and noninflammatory In this study, we report the results of a mutational analysis central stroma thinning. It is a major indication for corneal of the VSX1 gene performed in a series of unrelated Italian transplantation in the Western world,1,2 and its prevalence in patients affected by keratoconus. The VSX1 reference se- the general population is approximately 1:2000.3,4 quence is GenBank accession no. AF176797 (http://www. The disease arises in the teenage years with progressive ncbi.nlm.nih.gov/Genbank; provided in the public domain by myopia and astigmatism. In nearly all patients, keratoconus is the National Center for Biotechnology Information, Bethesda, an isolated defect, but in other cases it may be a finding in MD). syndromic conditions, as observed in Ehlers-Danlos, Marfan, Apert, Noonan, and Down syndromes. METHODS From the 1Medical Genetics Service and Ophthalmology Depart- Patients 2 ment, IRCCS-CSS Hospital, San Giovanni Rotondo (Fg), Italy; the Stu- Eighty Italian patients affected by keratoconus were recruited and, 3 dio Medico Associato, Chieti, Italy; the Department of Ophthalmol- after providing informed consent, enrolled in the study. The research ogy, University of Foggia, Foggia, Italy; the 4 Studio Oculistico, adhered to the tenets of the Declaration of Helsinki. Manfredonia (Fg), Italy; and the 5Department of Ophthalmology, Uni- versity of Parma, Parma, Italy. Fourteen participants with keratoconus belonged to families in Supported by the Italian Ministry of Health Ricerca Corrente which at least two keratoconus-affected subjects were present, 2002-2004. whereas the other 66 patients were isolated cases. The patients were Submitted for publication May 13, 2004; revised September 28, aged from 11 to 62 years; the first clinical diagnosis was made at ages 2004; accepted October 8, 2004. ranging from 9 to 43 years. Disclosure: L. Bisceglia, None; M. Ciaschetti, None; P. De Bo- The diagnosis of keratoconus was made on the basis of clinical nis, None; P.A.P. Campo, None; C. Pizzicoli, None; C. Scala, None; examination (corneal stromal thinning, Vogt’s striae, Fleischer’s ring, M. Grifa, None; P. Ciavarella, None; N. Delle Noci, None; F. Vaira, Munson’s sign), a history of penetrating keratoplasty for keratoconus, None; , None; , None C. Macaluso L. Zelante and corneal topography. In addition, corneal topographies of the The publication costs of this article were defrayed in part by page VSX1 charge payment. This article must therefore be marked “advertise- relatives of patients carrying mutations were evaluated with a ment” in accordance with 18 U.S.C. §1734 solely to indicate this fact. corneal analysis system (model 2000; Eye Sys Laboratories, Houston, Corresponding author: Leopoldo Zelante, Medical Genetics Ser- TX) to examine videokeratographic anomalies typical of clinical or vice, IRCCS-CSS Hospital, I-71013 San Giovanni Rotondo, Italy; subclinical keratoconus. According to the classification of Rabino- [email protected]. witz21 and Levy et al.,9 a color-coded map with 0.5-D increments was Investigative Ophthalmology & Visual Science, January 2005, Vol. 46, No. 1 Copyright © Association for Research in Vision and Ophthalmology 39 Downloaded from iovs.arvojournals.org on 10/02/2021 40 Bisceglia et al. IOVS, January 2005, Vol. 46, No. 1 used to define corneal shapes, and four indices: corneal power (K), affected by keratoconus and was inherited from his mother, inferior–superior dioptric asymmetry (I-S), astigmatism (Ast), and whose corneal topography shows an astigmatic, keratoconus- skewed radial axis (SRAX) were used to calculate KISA%, a single index suspect cornea, with a KISA% index of 76.9 in one eye (Table that quantifies the irregular corneal shape and astigmatism typical of 1). The mutation was not found in two normal brothers of the keratoconus with good clinical correlation.9–21 After the results of proband. several studies examining the relationship between the above-men- Case K2-II:1 was 28 years old and could be considered a tioned parameters and keratoconus,9–21-23 topography could be con- case of sporadic keratoconus, as his parents had a negative sidered keratoconus-suspect if the KISA% index is higher than 60% history (Fig. 2, Fam. K2). Patient K3-II:1 (Fig. 2, Table 1) and/or an AB/SRAX, J or inverted-J (Jinv) topographical pattern are showed the same mutation in a compound heterozygous state, present. along with the G160D allele, a mutation described in corneal One-hundred twenty-five subjects without ocular diseases were PPCD.20 In this pedigree, both his mother and brother were selected from the general population and used as the normal control. heterozygous for the L17P and showed keratoconus-suspect videokeratography, with a J pattern in at least one eye and a Mutational Search high KISA% index (Table 1). The mutation was not found in a normal relative. The father of the patient was clinically normal. DNA was extracted from peripheral blood by standard phenol-chloro- 3 form methodology and amplified in a final reaction volume of 25 ␮Lby The L17P mutation can be analyzed by PCR, since the T C ϫ transition at nucleotide 323 creates a new BsaHI restriction using 150 ng of genomic DNA, 10 PCR buffer with 15 mM MgCl2, 200 ␮M each dNTPs, 0.10 ␮M primers, and 1.0 U DNA polymerase (Am- site, leading to the formation of the 174- and 64-bp bands in the pliTaq Gold; Applied Biosystems [ABI], Foster City, CA). PCR cycling mutated allele after amplification with the 1F and 1yR primers, conditions consisted of an initial denaturation step at 95°C for 12 as described before (Fig. 1). Two previously unreported intronic nucleotide changes, minutes followed by 35 cycles of 94°C for 30 seconds, 58°C (exon 1), ϩ ϩ 59°C (exons 2, 4, 5), 62°C (exon 3) for 30 seconds, 72°C for 30 c.900 23A/G and c.900 84T/A, were found (Table 2). seconds and ending with a final elongation step at 72°C for 7 minutes. The primer pairs to amplify each of the five coding VSX1 exons were Previously Reported Sequence Variants designed by using the Primer 3 program24: exon 1 with 599-bp product The D144E allele was identified in two families (Fig. 2, Table 1 forward (F) (5Ј-CAGCTGATTGGAGCCCTTC-3Ј) and 1 reverse (R) 1). In family K4 the D144E allele was found in a 58-year-old (5Ј-CTCAGAGCCTAGGGGACAGG-3Ј); exon 2 with 393-bp product 2F subject who underwent corneal transplantation for bilateral (5Ј-GCACTAAAAATGCTGGCTCA-3Ј) and 2R (5Ј-GCCTCCTAGGAACT- keratoconus. The patient was heterozygous for the mutation, GCAGAA-3Ј); exon 3 with 419-bp product 3F (5Ј-CATTCAGAGGT- which was transmitted to his 22-year-old son whose clinical GGGGTGTT-3Ј) and 3R (5Ј-TCTTGTGGTGCCTTCAGCTA-3Ј); exon 4 examination showed with-the-rule astigmatism, but the subject with 394-bp product 4F (5Ј-GATCATGCTCGGGAGAGAAG-3Ј) and 4R was not available for videokeratographic testing.
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