Together, the known adRP genes account for retinal disease in approximately half of the families in this survey, mostly Americans of European origin. Among the adRP genes, IMPDH1, PRPF8, PRPF31, RDS, RHO, and RP1 each accounts for more than 2% of the total; CRX, PRPF3, and RPGR each accounts for roughly 1%. Disease-causing mutations were not found in CA4, FSCN2, NRL, or RP9. Because some mutations are frequent and some regions are more likely to harbor mutations than others, more than two thirds of the detected mutations can be found by screening less than 10% of the total gene sequences. Among the remaining families, mutations may lie in regions of known genes that were not tested, mutations may not be detectable by PCR-based sequencing, or other loci may be involved.

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.

Identification of unique retinal isoforms supports the existence of a novel IMPDH1 function in the retina, one that is probably altered by disease-causing mutations. This alone, or coupled with the high levels of IMPDH1 in the retina, may explain the retina-specific phenotype associated with IMPDH1 mutations. Elucidating the functional properties of these unique, human retinal isoforms is crucial to understanding the pathophysiology of IMPDH1 mutations.

No abstract

Objective Disulfiram is a potential cocaine addiction pharmacotherapy. Since dopamine deficiency has been found with cocaine addiction, our objective was to examine whether functional variants in the ankyrin repeat and kinase domain-containing 1 gene (ANKK1) and/or the dopamine receptor D2 gene (DRD2) interact with response to treatment with disulfiram. Methods Cocaine and opioid co-dependent (DSM-IV) patients were stabilized on methadone and subsequently randomized into treatment groups, disulfiram (250 mg/day, N = 31) or placebo (N = 37), genotyped for ANKK1 (rs1800497) and DRD2 (rs2283265) polymorphisms, and the data evaluated for association with cocaine-free urines in the presence or absence of disulfiram. Data was analyzed using repeated measures analysis of variance (ANOVA) corrected for population structure. Results Patients with CT or TT ANKK1 genotypes dropped from 80% to 52% cocaine-positive urines on disulfiram (N = 13; p = 0.0001) while those on placebo (N = 20) showed no treatment effect. Patients carrying the CC ANKK1 genotype showed no effect from disulfiram (N = 18) or placebo (N = 17). The GT/TT DRD2 genotype group showed a significant decrease in cocaine-positive urines on disulfiram (N = 9; 67% – 48%; p ≤ 0.0001), while the GG DRD2 genotype group showed a marginal decrease (N = 23; 84% – 63%; p = 0.04). Genotype pattern analysis revealed that individuals carrying at least one minor allele in either gene responded better to disulfiram treatment (N = 13; p ≤ 0.0001) than individuals carrying only the major alleles (N = 17). Conclusions A patient’s genotype for ANKK1, DRD2, or both, may be used to identify individuals for whom disulfiram may be an effective pharmacotherapy for cocaine dependence.