Mutation Survey of the IMPDH1 Gene in Patients With Autosomal Dominant Retinitis Pigmentosa and Review of the Clinical Findings Associated With IMPDH1 Mutations

Abstract

Abstract: : Purpose: To determine the frequency and types of mutations in the IMPDH1 gene among patients with autosomal dominant retinitis pigmentosa (ADRP) and to characterize the clinical features of patients with pathogenic mutations in this gene. Methods: The coding sequence and the adjacent flanking intron sequences of all 14 exons of the IMPDH1 gene were directly sequenced in 190 unrelated patients with ADRP. Most patients resided in the United States or Canada. Most of the patients had already been screened for mutations in other ADRP genes, such as RHO, RDS, RP1, NRL, RP11, RP13, and RP18, and patients with pathogenic mutations in those genes were not included in this study. The clinical findings evaluated at initial visit included visual acuity, visual field area on the Goldmann perimeter, full-field electroretinogram (ERG) amplitudes, and presence or absence of cataract and/or bone-spicule pigmentation. Results: A previously reported missense mutation, Asp226Asn (Bowne et al., Hum. Mol. Genet. 11:559-568, 2002), was identified in 6 of 190 unrelated ADRP patients from North America. One isocoding polymorphism was identified, Leu244Leu (CTG > CTC), with an allele frequency of 0.134. Clinical evaluation of 23 patients (probands and affected relatives) with the Asp226Asn mutation (ages 6-56 yrs) showed constricted fields and reduced ERGs. Many showed more loss of rod ERG function than cone ERG function. About 50% had cataract and/or bone spicule pigmentation. Some patients of the same age had markedly different clinical severity. Conclusions: After correcting for the fact that patients with identified mutations in some other ADRP genes were excluded from this study, we estimate that the missense mutation Asp226Asn accounts for approximately 2% of cases with ADRP in the United States and Canada. Although it has been reported that there is similar reduction of cone and rod function in patients with Asp226Asn mutation, our data suggests a disproportionate reduction of rod function.

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