Achromatopsia is a congenital, autosomal recessively inherited disorder characterized by a lack of color discrimination, low visual acuity (o0.2), photophobia, and nystagmus. Mutations in the genes for CNGA3, CNGB3, and GNAT2 have been associated with this disorder. Here, we analyzed the spectrum and prevalence of CNGB3 gene mutations in a cohort of 341 independent patients with achromatopsia. In 163 patients, CNGB3 mutations could be identified. A total of 105 achromats carried apparent homozygous mutations, 44 were compound (double) heterozygotes, and 14 patients had only a single mutant allele. The derived CNGB3 mutation spectrum comprises 28 different mutations including 12 nonsense mutations, eight insertions and/or deletions, five putative splice site mutations, and three missense mutations. Thus, the majority of mutations in the CNGB3 gene result in significantly altered and/or truncated polypeptides. Several mutations were found recurrently, in particular a 1 bp deletion, c.1148delC, which accounts for over 70% of all CNGB3 mutant alleles. In conclusion, mutations in the CNGB3 gene are responsible for approximately 50% of all patients with achromatopsia. This indicates that the CNGB3/ACHM3 locus on chromosome 8q21 is the major locus for achromatopsia in patients of European origin or descent.

Achromatopsia is an autosomal recessive disorder featuring total colour blindness, photophobia, reduced visual acuity and nystagmus. While mutations in the CNGA3 gene on chromosome 2q11 are responsible for achromatopsia in a subset of patients, previous linkage studies have localized another achromatopsia locus, ACHM3, on chromosome 8q21. Using achromatopsia families in which CNGA3 mutations have been excluded, we refined the ACHM3 locus to a 3.7 cM region enclosed by markers D8S1838 and D8S273. Two yeast artificial chromosome (YAC) contigs covering nearly the entire ACHM3 interval were constructed. Database searches with YAC content sequences identified two overlapping high throughput genomic sequencing phase (HTGS) entries which contained sequences homologous to the murine cng6 gene encoding the putative beta-subunit of the cone photoreceptor cGMP-gated channel. Using RT-PCR and RACE, we identified and cloned the human cDNA homologue, designated CNGB3, which encodes an 809 amino acid polypeptide. Northern blot analysis revealed a major transcript of approximately 4.4 kb specifically expressed in the retina. The human CNGB3 gene consists of 18 exons distributed over approximately 200 kb of genomic sequence. Analysis of the CNGB3 gene in achromats revealed six different mutations including a missense mutation (S435F), two stop codon mutations (R203X and E336X), a 1 bp and an 8 bp deletion (1148delC and 819-826del) and a putative splice site mutation of intron 13. The 1148delC mutation was identified recurrently in several families, and in total was present on 11 of 22 disease chromosomes segregating in our families.

Retinitis pigmentosa is the most common form of retinal degeneration and is heterogeneous both clinically and genetically. The autosomal dominant forms (ADRP) can be caused by mutations in 12 different genes. This report describes the first simultaneous mutation analysis of all the known ADRP genes in the same population, represented by 43 Italian families. This analysis allowed the identification of causative mutations in 12 of the families (28% of the total). Seven different mutations were identified, two of which are novel (458delC and 6901CRT (P2301S), in the CRX and PRPF8 genes, respectively). Several novel polymorphisms leading to amino acid changes in the FSCN2, NRL, IMPDH1, and RP1 genes were also identified. Analysis of gene prevalences indicates that the relative involvement of the RHO and the RDS genes in the pathogenesis of ADRP is less in Italy than in US and UK populations. As causative mutations were not found in over 70% of the families analysed, this study suggests the presence of further novel genes or sequence elements involved in the pathogenesis of ADRP. R etinitis pigmentosa is a clinically and genetically heterogeneous type of retinal degeneration which results in progressive loss of vision. It is characterised by abnormalities of the photoreceptors or the retinal pigment epithelium. Patients with this disorder typically develop night blindness, followed by constriction of the peripheral visual fields, bone spicule-like pigmentary deposits, and abnormal electroretinography (ERG). In the more advanced stages of the disease, there are intraretinal and preretinal clumps of black melanin pigment, attenuated retinal vessels, loss of retinal pigment epithelium, and pallor of the optic nerve.1 The time of onset of the disease varies from childhood to middle age.2 The incidence is estimated to be 1 in 4000-5000 people in Western populations.3 4 Inheritance can be autosomal dominant, autosomal recessive, X linked, or in rare cases as a digenic trait. However, in the majority of cases (about 50-60% in the white population) it is impossible to establish the pattern of inheritance, and these cases are defined as ''sporadic. '' 5-7 Autosomal dominant retinitis pigmentosa (ADRP) represents between 15% and 35% of all cases of the disorder, depending on the countries and the ethnic groups analysed, with the highest values being found in the USA 8 and the lowest in southern Europe.9 A previous study reported that the prevalence of ADRP in the Italian population is about 17%, 10 which is concordant with estimates from other studies carried out in southern Europe. 9 To date, 12 genes have been clearly associated with the pathogenesis of this condition (RETnet, http://www.sph.uth.tmc.edu/Retnet/disease.htm). The rhodopsin (RHO) gene is the most commonly involved in ADRP (25-50% of cases) followed by RP1 (5-10%), RDS (5%), and IMPDH1 (5-10%). These prevalence values were all derived from different and heterogeneous studies mostly carried out in American and British populations, 6 11 12 and a simultaneous ...

ABSTRACT.Purpose: The aim of this research was to study the relevance of long-term follow-up of electroretinographic oscillatory potentials (OPs) in predicting the onset of minimal non-proliferative diabetic retinopathy in insulin-dependent diabetes patients. Methods: A total of 80 insulin-dependent diabetics, with normal fundi and normal OPs at first examination, were followed prospectively for 10 years. Oscillatory potentials were measured and fundus examinations performed once or twice per year. Results: During follow-up, 35% of patients developed diabetic retinopathy after a mean disease duration of 12 ∫ 2 years. A decrease in OP amplitudes was seen in 46% of this group, but reductions were also seen in the 25% of patients whose fundi remained normal. Statistical analysis of best-fit survival curves shows a significant difference (p ∞0.001) in the point of Kaplan-Meiers' curve maximal linearity (TmaxS).Conclusions: It appears that eyes with reduced OP amplitude have a greater probability of developing diabetic retinopathy. Subnormal OP amplitudes are not proof of real concomitant visible vascular damage, but may reflect a predisposition to functional neurosensorial disorder.

The latency of pattern-reversal VEPs was studied in type I insulin-dependent diabetics without retinal and extraocular involvement. One hundred eyes of 50 diabetics (mean age 19.8 +/- 7.2 years) formed the study group; the duration of the disease ranged between 1 month and 15 years. The latencies of VEPs were progressively delayed in relation to the duration of the disease, becoming more and more evident and stabilizing after about 6 years from the onset of diabetes. The VEP alterations probably indicate alteration of membrane balance or demyelinization.