Spectrum and Frequency of Mutations in IMPDH1 Associated with Autosomal Dominant Retinitis Pigmentosa and Leber Congenital Amaurosis

Abstract

Mutations in IMPDH1 account for approximately 2% of families with adRP, and de novo IMPDH1 mutations are also rare causes of isolated LCA. This analysis of the novel IMPDH1 mutants substantiates previous reports that IMPDH1 mutations do not alter enzyme activity and demonstrates that these mutants alter the recently identified single-stranded nucleic acid binding property of IMPDH. Studies are needed to further characterize the functional significance of IMPDH1 nucleic acid binding and its potential relationship to retinal degeneration.

Retinal isoforms of inosine 5′-monophosphate dehydrogenase type 1 are poor nucleic acid binding proteins

“…The standard assay measures the fraction of a random oligonucleotide pool associated with protein on a nitrocellulose filter. The canonical IMPDH1 binds ~7% of the pool with K d = 6 nM [7,12]. However, 50 nM IMPDH1(546) binds only ~0.3% of the pool (Figure 4).…”

“…RP is often caused by mutations in photoreceptor-specific proteins, but can also result from mutations in widely expressed proteins such as IMPDH1 [4][5][6]. The most commonly occurring IMPDH1 mutation, D226N, accounts for 1-2.5% of all autosomal dominant RP cases [6][7][8]. Mutations in IMPDH1 also cause Leber congenital amaurosis (LCA), a more severe retinal degeneration [7].…”

“…The most commonly occurring IMPDH1 mutation, D226N, accounts for 1-2.5% of all autosomal dominant RP cases [6][7][8]. Mutations in IMPDH1 also cause Leber congenital amaurosis (LCA), a more severe retinal degeneration [7]. The pathophysiological mechanism of IMPDH1-linked adRP and the tissue specificity of disease are not understood.…”

“…First, the adRPlinked mutations of IMPDH1 have no effect on enzymatic activity [7,12]. Moreover, most of the mutations are located in a subdomain that is not required for enzymatic function [13,14].…”

“…We have discovered that IMPDH binds nucleic acids, and that this interaction is mediated by the subdomain [16]. The adRP-linked mutations perturb this nucleic binding function, decreasing both affinity and specificity of this interaction [7,12].…”