Mutations in IMPDH1 Are Associated With Leber Congenital Amaurosis

Abstract

Abstract: : Purpose: Our research has demonstrated that mutations in the IMPDH1 gene cause the RP10 form of autosomal dominant retinitis pigmentosa (adRP). Mutations in several adRP genes, such as peripherin/RDS, have been shown to cause other forms of retinal degeneration. The goal of this project was to determine if mutations in IMPDH1 cause forms of retinal degeneration other than adRP. Methods: DNA from 50 probands with autosomal recessive RP (arRP), 17 probands with macular degeneration (MD), 19 probands with isolated Leber congenital amaurosis (LCA), 4 probands with recessive LCA and 100 control individuals were tested for mutations in the IMPDH1 gene. The entire IMPDH1 coding sequence and flanking intron/exon junctions were analyzed by fluorescent PCR product sequencing. Results: An Asn198Lys IMPDH1 variant was found in one of the isolated LCA probands tested. Subsequent analysis of additional family members demonstrates that this is a "new" mutation not found in the proband’s unaffected parents. Parentage was confirmed by genotyping. An Arg105Trp mutation was also identified in another isolated LCA patient from our cohort. Neither of these IMPDH1 variants was found in any of the control individuals tested. Biochemical analysis of the Asn198Lys and Arg105Trp mutant proteins shows little effect on enzyme activity. Discussion: Our data suggest that mutations in IMPDH1 are a likely cause of LCA. Given the family history of the LCA probands and the inheritance pattern of adRP associated IMPDH1 mutations, it is likely that these "new" mutations will segregate in a dominant fashion. Studies are underway to analyze other functional properties of the IMPDH1 Arg198Lys and Arg105Trp mutant proteins.

Keywords: retinal degenerations: hereditary • gene mapping • genetics