Superoxide Dismutase 1 (SOD1)

SOD1 was identiÞed as a potential candidate gene in keratoconus due to its location on chromosome 21 and due to the fact that there is a higher prevalence of keratoconus in Down syndrome patients [21, 22]. Udar et al. [45] performed mutational analysis of SOD1 in 15 unrelated individuals with a family history of keratoconus. A seven base pair deletion in intron 2 of SOD1 (IVS2 + 50del7) was detected in two unrelated individuals with familial keratoconus, and absent from 156 control individuals. Segregation could be assessed in one family. RT-PCR on RNA extracted from the blood of one affected individual carrying the SOD1 intronic mutation and two control individuals showed the presence of two additional major splice variants associated with the intronic mutation. These splice variants lack either exon 2 or both exon 2 and 3 and are predicted to alter SOD1 levels and function [46]. SOD1 binds copper and zinc in a complex, CuZn-SOD, which is an essential antioxidant in the cornea [47]. Following this study, Udar et al. [48] reported that both families harbouring the SOD1 intronic deletion had distinct haplotypes suggesting the mutation developed independently in these two families. A second study in 113 Slovenian patients with sporadic and familial keratoconus failed to detect pathogenic variants in SOD1 associated with keratoconus [39]. In conclusion, the role of SOD1 mutations in keratoconus has not been Þrmly established.

Interleukin 1 (IL1) Superfamily

Interleukin 1 (IL1) has been proposed as a candidate gene for keratoconus [49]. Keratocyte apoptosis and stromal thinning in keratoconic corneas is triggered by the epithelial release of interleukin 1 (IL1) [49, 50]. Kim et al. [49] investigated 12 polymorphic sites in the IL1 gene cluster in 100 unrelated Korean keratoconus patients. Two SNPs in the promoter region of IL1B were signiÞcantly different between patient and control groups: −511 (rs16944) and −31 (rs1143627). The combination of the alleles (haplotype) −31*C and −511*T, was associated with an additive increased risk for keratoconus. These two promoter variants and the IL1B- 31 T/-511 C haplotype are associated with regulation of IL1a and IL1b production [49]. Interleukins are central modulators of the response to corneal injury and there is evidence they play a role in keratoconus.

Collagen Genes

Disruption of COL8A1 and COL8A2 in a knockout mouse model resulted in corneal thinning: keratoglobus [51]. COL8A2 is also mutated in both PPCD and FuchÕs endothelial corneal dystrophy [52]. Aldave et al. [53] screened COL8A2 and COL8A1 in 50 unrelated patients with keratoconus but failed to detect any pathological variants. Mutations in type IV collagens cause Alport syndrome, a triad of nephropathy, sensorineural deafness and eye features which include anterior lenticonus,