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Voltage-gated calcium channels (VGCC) are key to many biological functions. Entry of Ca2+into cells is essential for initiating or modulating important processes such as secretion, cell motility, and gene transcription. In the retina and other neural tissues, one of the major roles of Ca2+-entry is to stimulate or regulate exocytosis of synaptic vesicles, without which synaptic transmission is impaired. This review will address the special properties of one L-type VGCC,CaV1.4, with particular emphasis on its role in transmission of visual signals from rod and cone photoreceptors (hereafter called “photoreceptors,” to the exclusion of intrinsically photoreceptive retinal ganglion cells) to the second-order retinal neurons, and the pathological effects of mutations in theCACNA1Fgene which codes for the pore-formingα1Fsubunit ofCaV1.4.

X-linked congenital stationary night blindness (CSNB) is a recessive non-progressive retinal disorder characterized by night blindness, decreased visual acuity, myopia, nystagmus and strabismus. Two distinct clinical entities of X-linked CSNB have been proposed. Patients with complete CSNB show moderate to severe myopia, undetectable rod function and a normal cone response, whereas patients with incomplete CSNB show moderate myopia to hyperopia and subnormal but measurable rod and cone function. The electrophysiological and psychophysical features of these clinical entities suggest a defect in retinal neurotransmission. The apparent clinical heterogeneity in X-linked CSNB reflects the recently described genetic heterogeneity in which the locus for complete CSNB (CSNB1) was mapped to Xp11.4, and the locus for incomplete CSNB (CSNB2) was refined within Xp11.23 (ref. 5). A novel retina-specific gene mapping to the CSNB2 minimal region was characterized and found to have similarity to voltage-gated L-type calcium channel alpha1-subunit genes. Mutation analysis of this new alpha1-subunit gene, CACNA1F, in 20 families with incomplete CSNB revealed six different mutations that are all predicted to cause premature protein truncation. These findings establish that loss-of-function mutations in CACNA1F cause incomplete CSNB, making this disorder an example of a human channelopathy of the retina.

Background: Mutations in CACNA1F, which encodes the Cav1.4 subunit of a voltage-gated L-type calcium channel, cause X-linked incomplete congenital stationary night blindness (CSNB2), a condition of defective retinal neurotransmission which results in night blindness, reduced visual acuity, and diminished ERG b-wave. We have characterized two putative murine CSNB2 models: an engineered null-mutant, with a stop codon (G305X); and a spontaneous mutant with an ETn insertion in intron 2 of Cacna1f (nob2).

Colchicine resistant (CHR) mutants of CHO cells with reduced permeability to colchicine display extensive cross-resistance to a number of apparently unrelated compounds including puromycin, daunomycin, emetine, ethidium bromide and gramicidin D. A positive correlation was observed between the level of cross-resistance and the relative hydrophobicity of these compounds. The mutants also showed increased (collateral) sensitivity to local anaesthetics (procaine, tetracaine, xylocaine and propanolol), steroid hormones (1-dehydrotestosterone, corticosterone and 5beta-pregnan-3,20-dione) and some Triton X compounds. In general, the degree of the pleiotropic response (cross-resistance or collateral sensitivity) correlated with the degree of colchicine resistance in mutant lines. These results are consistent with the pleiotropic phenotype being the result of the same mutation(s) which confer colchicine resistance and support a model for resistance in which the reduced permeability is assumed to be the result of an alteration in the modulation of the fluidity of the surface membrane.

Four nuclear and two cytoplasmic chloramphenicol-resistance markers were selected in S. cerevisiae. The effect of the suppressive factor (abnormal mitochondria deoxyribonucleic acid) on the inheritance of these markers was studied. Nuclear markers were shown to be unaffected by the suppressive factor, in contrast to the loss of cytoplasmically inherited chloramphenicol resistance upon the generation of the suppressive factor.

Six ethidium bromide (EB) resistant mutants were isolated and characterized. The resistance in three isolates was stable, nuclearly inherited and sensitive to glucose repression. Unstable EB dependent resistance was present in the other isolates. The mutants with stable and one of those with unstable EB resistance showed cross resistance to the cationic detergent, cetyltrimethylammonium bromide. Both anaerobiosis and oligomycin inhibited EB induction of petites in the EB sensitive strain and in the EB-sensitized resistant strains. The observations are discussed in relationship to a mechanism of EB resistance and petite induction at the level of the mitochondrial membrane.

An unusual property of GR25a [rho+] was the production of 20 to 30 percent [rho−] zygote colonies when crossed to a tester strain lacking mitochondrial DNA. Spontaneous [rho−] isolates of GR25a [rho+] were observed to be highly suppressive and to contain mitochondrial DNA of a parental buoyant density (1.685 g/cm3). Three ethidium bromide induced neutral petites of GR25a [rho+] did not have detectable mitochondrial DNA and were neutral in crosses to [rho+] strains. Seven [rho−] zygote colony isolates obtained from crossing GR25a [rho+] to a neutral petite were shown to contain abnormal mitochondrial DNA. Six zygote colony isolates had mitochondrial DNA of a buoyant density less than, or equal to, GR25a (1.682–1.685 g/cm3), whereas one isolate had a buoyant density greater than GR25a (1.688 g/cm3). It was suggested that abnormal mitochondrial DNA is generated during the mating reaction.

The deleterious effects of many environmental agents--ultraviolet (UV) light, ionizing radiation, and polycyclic aromatic hydrocarbons, to cite a few--are primarily attributed to their ability to react with, and thereby structurally modify the deoxyribonucleic acid (DNA) of the living cell1. Given the appreciable level of damage believed to occur naturally in DNA2 and the need to maintain its fidelity as the repository of the genetic script, it s understandable that all living organisms, humans included, should possess multiple cellular processes whose combined actions promote the repair of damage to DNA3. An increasing number of genetically transmitted disorders in man is being found to be associated with enhanced sensitivity to extrinsic DNA-damaging agents. Patients afflicted with any one of these particular Mendelian single-gene traits are typically cancer-prone and suffer from progressive neurodegeneration, and, at least for a few disorders, their cells when cultured in vitro exhibit anomalies in one or more DNA epair processes4–8. The majority of these hereditary diseases can be divided into two broad groups: (i) disorders associated with hypersensitivity to UV light and UV-mimetic chemicals; and (ii) disorders associated with hypersensitivity to ionizing radiation and radiomimetic chemicals. Exemplary diseases of the former group--namely, xeroderma pigmentosum (XP), Bloom syndrome (BS), and Cockayne syndrome--are reviewed elsewhere in this volume. Here we present an overview of the clinical and laboratory features of the latter group of disorders with emphasis on the prototype disease, ataxia telangiectasia (AT)7,8, and comment briefly on current insight into the pathogenesis of these disorders and its implications for theories on environmental carcinogenesis and neurodegenerative processes in man.

Previous tetrad analyses defined a yeast strain (332-7c) as containing a single nuclear gene (11.8 map units from the centromere) conferring resistance to oligomycin. Resistance to 18 additional inhibitors of mitochondrial function (Table 1) was determined on (i) ascospore isolates from tetrads segregating 2 resistant: 2 sensitive for oligomycin (Table 2) and (ii), spontaneously derived sensitive isolates of the oligomycin resistant strain (Tables 3 and 4). The observed pattern of resistance suggests that the gene for resistance to oligomycin also results in (i) cross resistance to rutamycin, venturicidin, triethyltin bromide, antimycin A, carbonylcyanide m-chlorophenylhydrazone, tetra-N-butylammonium bromide, dibenzyl-dimethylammonium chlorop and tetracycline and (ii), collateral sensitivity to paromomycin, neomycin, dequalinium chloride, ethidium bromide and acriflavin.

Neutral petites were induced in three different [rho+] strains by treating with ethidium bromide. However, EB treatment of spontaneously generated suppressive petites, which were derived from the same [rho+] strains, produced no neutral petites and moreover had little or no effect on the suppressiveness of the petities. Genetic analysis showed that the ethidium bromide resistance of the suppressive petites was a manifestation of cytoplasmically inherited, respiratory deficiency.