Molecular Vision 2007; 13:1777-82 <http://www.molvis.org/molvis/v13/a198/> Received 22 August 2007 | Accepted 20 September 2007 | Published 24 September 2007 Schnyder crystalline corneal dystrophy (SCCD; OMIM 121800) is an autosomal dominantly inherited disorder that is characterized by corneal stromal cholesterol deposition, most commonly in an axially distributed, annular or discoid pattern with prominent arcus lipoides. While affected individuals dem- onstrate a higher prevalence of hypercholesterolemia than that observed in the general population, the majority of affected individuals do not have elevated serum cholesterol levels [1]. Affected individuals often require corneal transplantation for visual rehabilitation although laser phototherapeutic keratec- tomy has been reported to be of benefit in patients with cor- neal opacification primarily involving the anterior stroma [2,3]. The search for the genetic basis of SCCD began over 10 years ago with the performance of a genome-wide linkage analysis in two large affected families of Scandinavian de- scent [4]. Significant evidence of linkage to chromosome 1p24.1-p36 (now defined as 1p36.2-p36.3) was obtained in each family with haplotype analysis defining a 16 cM candi- date interval [5]. Fine mapping of this candidate region in these and 11 other affected families refined the SCCD locus to a 2.32 Mbp interval, containing 31 known and predicted genes (build 35.1) [5]. We have previously reported the absence of coding region mutations in 15 of the positional candidate genes in two families with SCCD [6]. Subsequently, we proceeded to screen the remaining positional candidate genes mapped to the 2.32 Mbp interval between the D1S1160 and D1S1635 markers. Although a large number of novel and previously identified sequence variants were identified in these genes, each was considered a polymorphism due to nonsegregation with the affected phenotype in the family identified with it and/or due to identification of the sequence variant in control individuals. Recently, Orr and colleagues [7] identified five different presumed missense mutations in the UbiA prenyltransferase domain containing gene (UBIAD1) in five families with SCCD. While UBIAD1 is located 368 Kbp centromeric to the D1S1635 marker that defines the centromeric border of the 2.32 Mbp fine mapped interval for SCCD, it is located within an over- lapping 1.3 Mbp candidate interval identified through the per- formance of linkage and haplotype analysis by Orr and col- leagues in a large family with SCCD [7]. As screening of UBIAD1 in the families linked to the original 2.32 Mbp fine ©2007 Molecular Vision Identification of mutations in UBIAD1 following exclusion of coding mutations in the chromosome 1p36 locus for Schnyder crystalline corneal dystrophy Vivek S. Yellore, M. Ali Khan, Nirit Bourla, Sylvia A. Rayner, Michael C. Chen, Baris Sonmez,Rominder S. Momi, Kapil M. Sampat, Michael B. Gorin, Anthony J. Aldave The Jules Stein Eye Institute, David Geffen School of Medicine at the University of California, Los Angeles, CA Purpose: To identify the genetic basis of Schnyder crystalline corneal dystrophy (SCCD) through screening positional candidate genes and UBIAD1, in which mutations have been associated with SCCD, in affected families. Methods: The coding region of each of the 16 positional candidate genes for which mutation screening has not been previously reported was screened with polymerase chain reaction (PCR) amplification and automated sequencing in four affected individuals from two families with SCCD. In addition, the coding region of UBIAD1, located just outside of the originally described SCCD candidate interval on chromosome 1p36, was directly sequenced in affected and unaffected individuals from three families with SCCD. Results: Eighteen novel and 15 previously reported sequence variants were identified in 10 of the 16 positional candidate genes. Only two of the sequence variants segregated with the affected phenotype in either of the families screened. Both were novel single nucleotide polymorphisms (SNPs) predicted to result in synonymous amino acid substitutions in differ- ent predicted genes. However, one of these SNPs was also identified in control individuals, and the other SNP was not predicted to alter splicing. Screening of UBIAD1 revealed a different missense mutation in each of the three unrelated probands that was screened: p.Asn102Ser, p.Arg119Gly, and p.Leu121Val. Screening of the affected and unaffected rela- tives of the probands in whom the p.Asn102Ser and p.Leu121Val mutations were identified demonstrated that each muta- tion segregated with the affected phenotype. None of the three missense mutations was identified in 110 control individu- als. Conclusions: No presumed pathogenic coding region mutations were identified in the genes mapped to the candidate region for SCCD. However, missense mutations in UBIAD1, located just outside of the originally described SCCD fine mapped region, were identified in each of the three families with SCCD, confirming that mutations in UBIAD1 are associated with SCCD. Correspondence to: Anthony J. Aldave, M.D., Associate Professor, The Jules Stein Eye Institute 100 Stein Plaza, Los Angeles, CA, 90095; Phone: (310) 206-7202; FAX: (310) 794-7906; email: aldave@jsei.ucla.edu 1777