Mutations in the gene encoding the alpha subunit of the rod cGMP-gated channel in autosomal recessive retinitis pigmentosa.

Abstract

Mutations in the genes encoding two proteins of the retinal rod phototransduction cascade, opsin and the j3 subunit of rod cGMP phosphodiesterase, cause retinitis pigmentosa (RP) in some families. Here we report defects in a third member of this biochemical pathway in still other patients with this disease. We screened 94 unrelated patients with autosomal dominant RP and 173 unrelated patients with autosomal recessive RP for mutations in the gene encoding the a subunit of the rod cGMP-gated cation channel. Five mutant sequences cosegregated with disease among four unrelated families with autosomal recessive RP. Two of these were nonsense mutations early in the reading frame (Glu76End and Lysl39End) and one was a deletion encompassing most if not all of the transcriptional unit; these three alleles would not be expected to encode a functional channel. The remaining two mutations were a missense mutation (Ser316Phe) and a frameshift [Arg654(1-bp del)] mutation truncating the last 32 aa in the C terminus. The latter two mutations were expressed in vitro and found to encode proteins that were predominantly retained inside the cell instead ofbeing targeted to the plasma membrane. We conclude that the absence or paucity of functional cGMP-gated cation channels in the plasma membrane is deleterious to rod photoreceptors and is an uncommon cause of RP.Retinitis pigmentosa (RP) is a genetically heterogeneous set of diseases in which affected individuals develop progressive degeneration of the rod and cone photoreceptors. Patients typically experience night blindness by age 20 followed by progressive loss of peripheral visual field and later central visual field that leads to blindness usually in middle age. Oral vitamin A supplementation slows the course of the disease in most cases (1). Dominant, recessive, X chromosome-linked, and digenic patterns of inheritance are exemplified by families with RP, and even among the families with the same inheritance pattern, there is nonallelic heterogeneity. More than 15 genes have been implicated by linkage studies, five of which have been identified to date. Two of these genes encode proteins known to function in the phototransduction pathway [namely, rhodopsin (2) and the ,3 subunit of rod cGMPphosphodiesterase (3)], two are photoreceptor-specific proteins of unknown function [peripherin/RDS (4-6) and ROM1 (6)], and one is an unconventional myosin (7).Here we report the analysis of the gene encoding the a subunit of the rod cGMP-gated cation channel, which is the protein involved in the last stage of the phototransduction pathway (for review, see ref. 8). The rod cGMP-gated cation channel is a heterooligomer composed of two homologous subunits (a and (3), each with cytoplasmic N and C termini, six putative transmembrane domains, and a pore region (9-11).

Why photoreceptors die (and why they don't)

“…In a similar fashion, rods degenerate in animals (including humans) that lack functional cGMP-gated channels. (64,65) The knocking out of the channels should also cause a maintained lowering of the Ca 2þ concentration, since the entry pathway for Ca 2þ into the outer segment is eliminated, but there is one difficulty with this notion. The channel in the outer segment is tightly associated with the Na þ /Ca 2þ -K þ exchange protein, (66,67) with two exchanger molecules bound to each channel heteromer.…”

Molecular cloning, functional expression and chromosomal localization of a human homolog of the cyclic nucleotide‐gated ion channel of retinal cone photoreceptors

“…The chromosomal localization will be useful in the search of candidate genes for retinal disorders. Mutations in the rod channel c~-subunit have been linked to certain cases of autosomal recessive retinitis pigmentosa, characterized by a degeneration of the rod photoreceptors [36]. It may be clinically relevant to know whether mutations in the cone channel gene can lead to cone-specific diseases.…”

“…The knowledge of the sequence and gene location will provide a useful basis for examining human diseases involving this channel gene. In the retina, mutations in the rod CNG channel have been shown to lead to certain cases of autosomal recessive retinitis pigmentosa [36]. At the same time, we were curious to know whether the human cone channel (c~-subunit) is sensitive to Ca2+-calmodulin as reported for the bovine homolog.…”

Nonarteritic anterior ischemic optic neuropathy with PDE-5 inhibitors for erectile dysfunction

“…9 It is of interest to note that some recessively inherited forms of retinitis pigmentosa, a common degenerative retinal disease, are caused by mutations in PDE-6. 12 In mice heterozygous for a mutation causing absence of the g-subunit of PDE-6, it was found that reversible dose-dependent ERG changes occurred following treatment with sildenafil. 13 Although further study is required, these findings imply that PDE-5 inhibitors could have a significant impact on retinal function in patients with retinitis pigmentosa and even in carriers of PDE-6 mutations.…”