Mutation Screening of the ESRRB Gene in Patients With Leber Congenital Amaurosis and Autosomal Recessive Retinitis Pigmentosa

Abstract

Abstract: : Purpose: To survey patients with autosomal recessive retinitis pigmentosa (ARRP) and Leber congenital amaurosis (LCA) for mutations in the ESRRB (estrogen-related receptor beta) gene located on chromosome 14q24.3. ESRRB is a member of the nuclear hormone receptor family and was chosen as a candidate for retinal degeneration since it is highly expressed in the retina and because a locus for LCA (LCA3) was assigned to chromosome 14q24 through linkage analysis (Stockton et al., Hum Genet 103:328-333, 1998). Methods: Oligonucleotide primers based on the flanking intron sequences were designed with the PRIMER3 program; they amplify each of the 8 coding exons and the 3 non-coding exons. We are analyzing an affected member of the LCA3-linked family along with 128 patients with ARRP and 56 patients with LCA. Some amplified fragments are being examined using single-strand conformation analysis while others are directly sequenced. Results: A missense change, Arg6Gly (AGG>GGG) was found heterozygously in two patients, one with LCA (patient 048-056) and one with ARRP (003-148). Evaluation of closely linked polymorphisms showed that patient 003-148 and an affected sibling received an identical set of alleles from the parents and all four unaffected siblings received a different pair of alleles. In a search for a second possible mutation on the homologous allele, all coding exons have been sequenced in patients 048-056 and 003-148, and no likely pathogenic changes were found. No mutations have been found in the affected LCA3 family member in any of the 8 coding exons. Non-coding exons are currently being evaluated. Likely non-pathogenic variants that have been found to date include IVS4+64T>C, IVS4+56T>C, IVS7+55C>T, IVS7+190C>T, IVS7-45G>C, IVS7+187A>C, Ile27Ile:ATA>ATC, Leu47Leu:CTG>CTC, and Val117Val:GTG>GTA. Conclusions: The cosegregation of ESRRB alleles in one small family with ARRP raises the possibility that this gene is a cause of ARRP. This gene is being further evaluated to determine if ESRRB has a role in causing retinal degeneration.

Keywords: retinal degenerations: hereditary • mutations • candidate gene analysis