Retinitis Pigmentosa 46
A number sign (#) is used with this entry because of evidence that retinitis pigmentosa-46 (RP46) is caused by homozygous mutation in the isocitrate dehydrogenase 3B gene (IDH3B; 604526) on chromosome 20p13.
For a phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.
Clinical FeaturesHartong et al. (2008) provided results of an ophthalmologic examination of 2 individuals with autosomal recessive IDH3B-related retinitis pigmentosa. The index case and the other individual, identified in a screen of patients with recessive or simplex retinitis pigmentosa, were evaluated at ages 47 and 38 years, respectively. Both had subnormal visual acuities, concentrically constricted visual fields, fundi typical of retinitis pigmentosa (pale optic discs, attenuated arterioles, and intraretinal pigment deposits), impaired dark adaptation, and reduced electroretinogram amplitudes indicating substantial loss of rod and cone photoreceptor function. They reported no other relevant health problems and, in particular, no problems typically associated with mitochondrial dysfunction such as reduced muscle strength, cardiac dysrhythmias, or reduced athletic stamina.
Molecular GeneticsIn an individual with retinitis pigmentosa and in her affected brother, Hartong et al. (2008) found homozygosity for a 1-basepair deletion in codon 197 of the IDH3B gene (604526.0001). The parents of the affected individual were first cousins; 4 of the unaffected sibs were heterozygous, and 1 was wildtype. Hartong et al. (2008) subsequently sequenced all 12 exons of the IDH3B gene in 261 individuals with recessive retinitis pigmentosa and 285 individuals with simplex retinitis pigmentosa (most of whom were presumed to have autosomal recessive retinitis pigmentosa). One individual was homozygous for a missense mutation (L98P; 604526.0002). This individual's parents were first cousins, and the individual's 3 sibs, all unaffected, were heterozygous. Neither mutation was identified after screening leukocyte DNA from 95 control individuals without retinitis pigmentosa. The IDH3B gene encodes the beta subunit of nicotinamide adenine dinucleotide-specific isocitrate dehydrogenase (NAD-IDH), which catalyzes the oxidation of isocitrate to alpha-ketoglutarate in the citric acid cycle. Cells from affected individuals had a substantial reduction of NAD-IDH activity, with about a 300-fold increase of the Michaelis constant (Km) for NAD. NADP-IDH (IDH2; 147650), an enzyme that catalyzes the same reaction as NAD-IDH, was normal in the affected individuals. These findings supported the hypothesis that mitochondrial NADP-IDH, rather than NAD-IDH, serves as the main catalyst for this reaction in the citric acid cycle outside the retina, and that the retina has a particular requirement for NAD-IDH.