Mutations in the UBIAD1 gene, encoding a potential prenyltransferase, are causal for Schnyder crystalline corneal dystrophy

Abstract

Schnyder crystalline corneal dystrophy (SCCD, MIM 121800) is a rare autosomal dominant disease characterized by progressive opacification of the cornea resulting from the local accumulation of lipids, and associated in some cases with systemic dyslipidemia. Although previous studies of the genetics of SCCD have localized the defective gene to a 1.58 Mbp interval on chromosome 1p, exhaustive sequencing of positional candidate genes has thus far failed to reveal causal mutations. We have ascertained a large multigenerational family in Nova Scotia affected with SCCD in which we have confirmed linkage to the same general area of chromosome 1. Intensive fine mapping in our family revealed a 1.3 Mbp candidate interval overlapping that previously reported. Sequencing of genes in our interval led to the identification of five putative causal mutations in gene UBIAD1, in our family as well as in four other small families of various geographic origins. UBIAD1 encodes a potential prenyltransferase, and is reported to interact physically with apolipoprotein E. UBIAD1 may play a direct role in intracellular cholesterol biochemistry, or may prenylate other proteins regulating cholesterol transport and storage.

Figure 1. Slit lamp image of the right cornea from a 50-year old affected member of family 105, demonstrating a “bull's eye” morphology of central and peripheral corneal clouding associated with a relatively spared mid-peripheral zone.

Central subepithelial crystalline deposits and prominent corneal arcus are also present.

Figure 2. SCCD pedigrees.

a) Family F105, showing affection status (filled symbols) and phased haplotypes generated by Simwalk for selected markers in the linked chromosomal region. Flanking recombinants in markers 10_55 and 11_752 are indicated. Genders are anonymized to preserve patient confidentiality. b) Family F115, showing affection status (filled symbols).

Figure 3. Multipoint linkage analysis using Simwalk for Family F105 (ped 1 in the figure) and F115 (ped 115 in the figure), across the linked chromosomal interval.

In this analysis individual 1443 of family 105 was set as phenotype unaffected; the maxLOD increased slightly to 9.5 when 1443 was set to phenotype unknown. A maxLOD = 6.6 was obtained using an affecteds-only model.

Figure 4. ClustalW alignment of vertebrate and invertebrate UBIAD1 putative orthologs.

The five familial mutations are highlighted in yellow above the mutated residue.

Figure 5. Conserved amino acid residues in three regions of UBIAD1 containing familial mutations (CS1, CS2, CS3).

Also shown are two regions aligning with putative bacterial UbiA active sites (AS1, AS2), which are overlapped with CS1 and CS3, respectively. Familial mutations plus the control variant detected in this study are highlighted in yellow above each consensus plot. The sequence logo was generated with the multiple sequence alignment of distant orthologs selected from Eukaryota, Bacteria, and Archaea. The pairwise alignment of human UBIAD1 and E.coli UbiA peptide sequences aligned by ClustalW was used to annotate the regions of putative active sites.

Figure 6. Predicted UBIA prenyltransferase domain-containing protein 1 structure from ModBase mapped with evolutionary conservation scores calculated by ConSurf.

Five familial mutations plus one control variant detected in this study are indicated. The color scale ranging from blue to red represents the conservation score of residue varies from 9 (most conserved) to 1 (most variable). a, Front view; b, Rear view.