Identification of STRA6 and SKI sequence variants in patients with anophthalmia/microphthalmia

Purpose: Anophthalmia and microphthalmia (A/M) are rare congenital ocular malformations presenting with the absence of eye components or small eyes with or without structural abnormalities. A/M can be isolated or syndromic. The stimulated by retinoic acid gene 6 (STRA6) and Sloan-Kettering viral oncogene homolog (SKI) genes are involved in vitamin A metabolism, and are implicated with A/M developmental abnormalities in human and animal studies. Vitamin A metabolism is vital to normal eye development and growth. This study explores the association of these genes in a cohort of subjects with A/M. Methods: STRA6 and SKI were screened for sequence variants by direct sequencing of genomic DNA samples from 18 affected subjects with A/M. The DNA samples of 4 external, unrelated controls were initially screened. Eighty-nine additional unrelated controls were screened to confirm that any sequence variants found in the affected subject DNA samples were related to the phenotype. Coding regions, intron-exon boundaries, and untranslated regions were sequenced by standard techniques. Derived DNA sequences were compared to known reference sequences from public genomic databases. Results: For STRA6, a novel coding non-synonymous sequence variant was found in one subject, resulting in an amino acid change from glycine to glutamic acid in residue 217. One novel nonsense sequence variant found in the same subject changed the STRA6 amino acid residue 592 from cytosine to thymine resulting in a premature stop codon. For SKI, a known coding non-synonymous sequence variant (rs28384811) was found in 3 subject DNA samples and 11/89 control DNA samples. Four novel coding-synonymous sequence variants were observed in SKI. Conclusions: The STRA6 sequence variants reported in this study could play a role in the pathogenesis of A/M by structural changes to the STRA6 protein. We can attribute 4% A/M incidence in this cohort to these sequence variants. Although no SKI sequence variants were found in this cohort, SKI should not be ruled out as a candidate gene for A/M due to the small cohort size. Anophthalmia and microphthalmia (A/M) are rare congenital ocular malformations presenting with the absence of eye components (anophthalmia) or small eyes with or without structural abnormalities (microphthalmia). A/M has a prevalence of approximately 30 per 100,000 population [1-3], or 70 incidents per 480,000 live births in the United States [4]. A/M may be isolated or syndromic with varied patterns of inheritance. Many genetic loci are associated with either isolated or syndromic A/M. To date, there are 3 genetic loci identified for isolated A/M; MCOP1 (14q32; OMIM 251600), MCOP2 (14q24.3; OMIM 610093), MCOP3 (18q21.3; OMIM 601881). In addition, there are 10 loci identified for syndromic A/M; MCOPS1 (Xq27–28; OMIM