Screen of the IMPDH1 gene among patients with dominant retinitis pigmentosa and clinical features associated with the most common mutation, Asp226Asn.
OBJECTIVE
To determine the frequency of mutations in IMPDH1 among patients with autosomal dominant retinitis pigmentosa (RP), to characterize the clinical features of patients with the Asp226Asn mutation in this gene, and to compare these features with those found among patients with selected dominant mutations in other RP genes.


METHODS
The coding sequence and the adjacent flanking intron sequences of all 14 coding exons were sequenced in 183 unrelated patients with dominant RP. The clinical findings evaluated included visual acuity, refractive error, visual field area measured with the Goldmann perimeter, final dark-adaptation threshold, full-field electroretinogram (ERG) amplitudes, cataract, and funduscopic bone spicule pigmentation.


RESULTS
The mutation Asp226Asn was identified in 6 of the 183 unrelated patients with RP. One patient carried the novel, possibly pathogenic, change Lys238Glu. There was approximately a 100-fold variation in ERG amplitudes among patients of similar age with the Asp226Asn mutation. Patients had similar reductions of rod-plus-cone 0.5-Hz ERG amplitude and cone 30-Hz ERG amplitude. For a given amount of remaining visual field, there was a larger ERG amplitude in IMPDH1-carrying patients (average 0.5-Hz ERG/visual field ratio = 9.5 nV/deg(2)) compared with groups of patients with the RP1 mutation Arg677End (2.8 nV/deg(2)), the rhodopsin (RHO) mutation Pro23His (5.1 nV/deg(2)), or the RHO mutation Pro347Leu (1.7 nV/deg(2)).


CONCLUSIONS
IMPDH1 mutations account for approximately 2% of cases of dominant RP in North America. The most frequent mutation, Asp226Asn, appears to cause at least as much loss of rod function as cone function. Patients with this form of RP retain, on average, two to five times more ERG amplitude per unit of remaining visual area than patients with three other forms of dominant RP.
Wada
Yuko
Y
The Ocular Molecular Genetics Institute, Harvard Medical School, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114, USA.
Sandberg
Michael A
MA
McGee
Terri L
TL
Stillberger
Melissa A
MA
Berson
Eliot L
EL
Dryja
Thaddeus P
TP
D000293:Adolescent; D000328:Adult; D002648:Child; D003623:Dark Adaptation; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D005799:Genes, Dominant; D005820:Genetic Testing; D006801:Humans; D007168:IMP Dehydrogenase / Q000235:genetics*; D008297:Male; D008869:Microtubule-Associated Proteins; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D012030:Refractive Errors; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000235:genetics*; D014792:Visual Acuity; D014794:Visual Fields
D005136:Eye Proteins; D008869:Microtubule-Associated Proteins; C120042:RP1 protein, human; D007168:IMP Dehydrogenase; C488211:IMPDH1 protein, human