Family poverty over the early life course and adult experiences of intimate partner violence: a cohort study.

OBJECTIVES: This study aimed to determine whether family poverty over the early childhood, adolescent, and adult periods of the life course independently predicts experiences of intimate partner violence (IPV) in adulthood. STUDY DESIGN: This was a birth cohort study in Brisbane, Australia, with pregnant women recruited at their first booking-in visit and their children, followed up to 30 and 40 years of age. METHODS: Family income was obtained from the mother when the child was 6 months, 5 and 14 years of age. Offspring reported their own family income at 21, 30, and 40 years of age. The offspring completed the Composite Abuse Scale at 30 and 40 years. Adjusted logistic regression models are used to predict experiences of IPV at 30 (n = 2157) and 40 (n = 1438) years. RESULTS: The findings at 30 and 40 years of age are consistent. Only poverty experienced concurrently with the assessment of IPV is strongly associated. At the 40-year follow-up, family poverty predicts higher ratios of all four forms of IPV; severe combined abuse (odds ratio [OR] = 2.24, 95% confidence interval [CI] = 1.24, 4.05), physical abuse (OR = 3.37, 95% CI = 1.95, 5.82), emotional abuse (OR = 2.09, 95% CI = 2.58, 8.57) and harassment (OR = 4.70, 95% CI = 2.58, 8.57). CONCLUSION: Concurrent family poverty is strongly and consistently associated with patterns of IPV. These associations are for cross-sectionally collected data with the prospectively collected data not replicating these findings. Although it is not possible to identify a specific causal pathway, the findings suggest that the immediate consequences of poverty are strongly associated with IPV. Programmes that address poverty reduction provide the best prospect for reducing societal levels of IPV.

Benchmarking Adaptive Steered Molecular Dynamics (ASMD) on CHARMM Force Fields.

The potentials of mean force (PMFs) along the end-to-end distance of two different helical peptides have been obtained and benchmarked using the adaptive steered molecular dynamics (ASMD) method. The results depend strongly on the choice of force field driving the underlying all-atom molecular dynamics, and are reported with respect to the three most popular CHARMM force field versions: c22, c27 and c36. Two small peptides, ALA 10 and 1PEF, serve as the particular case studies. The comparisons between the versions of the CHARMM force fields provides both a qualitative and quantitative look at their performance in forced unfolding simulations in which peptides undergo large changes in structural conformations. We find that ASMD with the underlying c36 force field provides the most robust results for the selected benchmark peptides.

Proposed cutoff for fetal scalp blood lactate in intrapartum fetal surveillance based on neonatal outcomes: a large prospective observational study.

OBJECTIVE: Determination of lactate in fetal scalp blood (FBS) during labour has been recognised since the 1970s. The internationally accepted cutoff of >4.8 mmol/l indicating fetal acidosis is exclusive for the point-of-care device (POC) LactatePro™, which is no longer in production. The aim of this study was to establish a new cutoff for scalp lactate based on neonatal outcomes with the use of the StatstripLactate® /StatstripXpress® Lactate system, the only POC designed for hospital use. DESIGN: Observational study. SETTING: January 2016 to March 2020 labouring women with indication for FBS were prospectively included from seven Swedish and one Australian delivery unit. POPULATION: Inclusion criteria: singleton pregnancy, vertex presentation, ≥35+0 weeks of gestation. METHOD: Based on the optimal correlation between FBS lactate and cord pH/lactate, only cases with ≤25 minutes from FBS to delivery were included in the final calculations. MAIN OUTCOME MEASURES: Metabolic acidosis in cord blood defined as pH <7.05 plus BDecf >10 mmol/l and/or lactate >10 mmol/l. RESULTS: A total of 3334 women were enrolled of whom 799 were delivered within 25 minutes. The areas under the receiver operating characteristics curves (AUC) and corresponding optimal cutoff values were as follows; metabolic acidosis AUC 0.87 (95% CI 0.77-0.97), cutoff 5.7 mmol/l; pH <7.0 AUC 0.83 (95% CI 0.68-0.97), cutoff 4.6 mmol/l; pH <7.05 plus BDecf ≥12 mmol/l AUC 0.97 (95% CI 0.92-1), cutoff 5.8 mmol/l; Apgar score <7 at 5 minutes AUC 0.74 (95% CI 0.63-0.86), cutoff 5.2 mmol/l; and pH <7.10 plus composite neonatal outcome AUC 0.76 (95% CI 0.67-0.85), cutoff 4.8 mmol/l. CONCLUSION: A scalp lactate level <5.2 mmol/l using the StatstripLactate® /StatstripXpress® system will safely rule out fetal metabolic acidosis. TWEETABLE ABSTRACT: Scalp blood lactate <5.2 mmol/l using the StatstripLactate® /StatstripXpress system has an excellent ability to rule out fetal acidosis.

Identification of Zika Virus Inhibitors Using Homology Modeling and Similarity-Based Screening to Target Glycoprotein E.

The World Health Organization has designated Zika virus (ZIKV) as a dangerous, mosquito-borne pathogen that can cause severe developmental defects. The primary goal of this work was identification of small molecules as potential ZIKV inhibitors that target the viral envelope glycoprotein (ZIKV E) involved in membrane fusion and viral entry. A homology model of ZIKV E containing the small molecule ß-octyl glucoside (BOG) was constructed, on the basis of an analogous X-ray structure from dengue virus, and >4 million commercially available compounds were computationally screened using the program DOCK6. A key feature of the screen involved the use of similarity-based scoring to identify inhibitor candidates that make similar interaction energy patterns (molecular footprints) as the BOG reference. Fifty-three prioritized compounds underwent experimental testing using cytotoxicity, cell viability, and tissue culture infectious dose 50% (TCID50) assays. Encouragingly, relative to a known control (NITD008), six compounds were active in both the cell viability assay and the TCID50 infectivity assay, and they showed activity in a third caspase activity assay. In particular, compounds 8 and 15 (tested at 25 µM) and compound 43 (tested at 10 µM) appeared to provide significant protection to infected cells, indicative of anti-ZIKV activity. Overall, the study highlights how similarity-based scoring can be leveraged to computationally identify potential ZIKV E inhibitors that mimic a known reference (in this case BOG), and the experimentally verified hits provide a strong starting point for further refinement and optimization efforts.

Alchemical Binding Free Energy Calculations in AMBER20: Advances and Best Practices for Drug Discovery.

Predicting protein-ligand binding affinities and the associated thermodynamics of biomolecular recognition is a primary objective of structure-based drug design. Alchemical free energy simulations offer a highly accurate and computationally efficient route to achieving this goal. While the AMBER molecular dynamics package has successfully been used for alchemical free energy simulations in academic research groups for decades, widespread impact in industrial drug discovery settings has been minimal because of the previous limitations within the AMBER alchemical code, coupled with challenges in system setup and postprocessing workflows. Through a close academia-industry collaboration we have addressed many of the previous limitations with an aim to improve accuracy, efficiency, and robustness of alchemical binding free energy simulations in industrial drug discovery applications. Here, we highlight some of the recent advances in AMBER20 with a focus on alchemical binding free energy (BFE) calculations, which are less computationally intensive than alternative binding free energy methods where full binding/unbinding paths are explored. In addition to scientific and technical advances in AMBER20, we also describe the essential practical aspects associated with running relative alchemical BFE calculations, along with recommendations for best practices, highlighting the importance not only of the alchemical simulation code but also the auxiliary functionalities and expertise required to obtain accurate and reliable results. This work is intended to provide a contemporary overview of the scientific, technical, and practical issues associated with running relative BFE simulations in AMBER20, with a focus on real-world drug discovery applications.

Structure-based identification of inhibitors targeting obstruction of the HIVgp41 N-heptad repeat trimer.

The viral protein HIVgp41 is an attractive and validated drug target that proceeds through a sequence of conformational changes crucial for membrane fusion, which facilitates viral entry. Prior work has identified inhibitors that interfere with the formation of a required six-helix bundle, composed of trimeric C-heptad (CHR) and N-heptad (NHR) repeat elements, through blocking association of an outer CHR helix or obstructing formation of the inner NHR trimer itself. In this work, we employed similarity-based scoring to identify and experimentally characterize 113 compounds, related to 2 small-molecule inhibitors recently reported by Allen et al. (Bioorg. Med. Chem Lett.2015, 25 2853-59), proposed to act via the NHR trimer obstruction mechanism. The compounds were first tested in an HIV cell-cell fusion assay with the most promising evaluated in a second, more biologically relevant viral entry assay. Of the candidates, compound #11 emerged as the most promising hit (IC50=37.81µM), as a result of exhibiting activity in both assays with low cytotoxicity, as was similarly seen with the known control peptide inhibitor C34. The compound also showed no inhibition of VSV-G pseudotyped HIV entry compared to a control inhibitor suggesting it was specific for HIVgp41. Molecular dynamics simulations showed the predicted DOCK pose of #11 interacts with HIVgp41 in an energetic fashion (per-residue footprints) similar to the four native NHR residues (IQLT) which candidate inhibitors were intended to mimic.

Defective hydrophobic sliding mechanism and active site expansion in HIV-1 protease drug resistant variant Gly48Thr/Leu89Met: mechanisms for the loss of saquinavir binding potency.

HIV drug resistance continues to emerge; consequently, there is an urgent need to develop next generation antiretroviral therapeutics.1 Here we report on the structural and kinetic effects of an HIV protease drug resistant variant with the double mutations Gly48Thr and Leu89Met (PRG48T/L89M), without the stabilizing mutations Gln7Lys, Leu33Ile, and Leu63Ile. Kinetic analyses reveal that PRG48T/L89M and PRWT share nearly identical Michaelis-Menten parameters; however, PRG48T/L89M exhibits weaker binding for IDV (41-fold), SQV (18-fold), APV (15-fold), and NFV (9-fold) relative to PRWT. A 1.9 Å resolution crystal structure was solved for PRG48T/L89M bound with saquinavir (PRG48T/L89M-SQV) and compared to the crystal structure of PRWT bound with saquinavir (PRWT-SQV). PRG48T/L89M-SQV has an enlarged active site resulting in the loss of a hydrogen bond in the S3 subsite from Gly48 to P3 of SQV, as well as less favorable hydrophobic packing interactions between P1 Phe of SQV and the S1 subsite. PRG48T/L89M-SQV assumes a more open conformation relative to PRWT-SQV, as illustrated by the downward displacement of the fulcrum and elbows and weaker interatomic flap interactions. We also show that the Leu89Met mutation disrupts the hydrophobic sliding mechanism by causing a redistribution of van der Waals interactions in the hydrophobic core in PRG48T/L89M-SQV. Our mechanism for PRG48T/L89M-SQV drug resistance proposes that a defective hydrophobic sliding mechanism results in modified conformational dynamics of the protease. As a consequence, the protease is unable to achieve a fully closed conformation that results in an expanded active site and weaker inhibitor binding.

Mutations in a gene encoding a new oxygen-regulated photoreceptor protein cause dominant retinitis pigmentosa.

The autosomal dominant retinitis pigmentosa (RP) locus, designated RP1, has been mapped through linkage studies to a 4-cM interval at 8q11-13. Here we describe a new photoreceptor-specific gene that maps in this interval and whose expression is modulated by retinal oxygen levels in vivo. This gene consists of at least 4 exons that encode a predicted protein of 2,156 amino acids. A nonsense mutation at codon 677 of this gene is present in approximately 3% of cases of dominant RP in North America. We also detected two deletion mutations that cause frameshifts and introduce premature termination codons in three other families with dominant RP. Our data suggest that mutations in this gene cause dominant RP, and that the encoded protein has an important but unknown role in photoreceptor biology.

A null mutation in the rhodopsin gene causes rod photoreceptor dysfunction and autosomal recessive retinitis pigmentosa.

Mutations within the rhodopsin gene are known to give rise to autosomal dominant retinitis pigmentosa (RP), a common hereditary form of retinal degeneration. We now describe a patient with autosomal recessive RP who is homozygous for a nonsense mutation at codon 249 within exon 4 of the rhodopsin gene. This null mutation, the first gene defect identified in autosomal recessive retinitis pigmentosa, should result in a functionally inactive rhodopsin protein that is missing the sixth and seventh transmembrane domains including the 11-cis-retinal attachment site. We also found a different null mutation carried heterozygously by an unrelated unaffected individual. Heterozygous carriers of either mutation had normal ophthalmologic examinations but their electroretinograms revealed an abnormality in rod photoreceptor function.

Public engagement in neighbourhood level wildfire mitigation and preparedness: case studies from Canada, the US and Australia.

This study examined neighbourhood level wildfire mitigation programs being implemented in neighbourhoods in Canada (FireSmart-ForestWise), Australia (Community Fireguard) and the US (Firewise Communities). Semi-structured interviews were completed with 19 residents participating in the programs. A wide range of activities were completed as part of the three programs. Despite differences between the three programs, participants appeared to participate in the programs for three main reasons: Fire experience, agency involvement, and personal and family protection. A fire therefore provides a window of opportunity to engage residents in neighbourhood level wildfire mitigation programs. The neighbourhood level wildfire mitigation programs helped to reduce the wildfire risk, but also enhanced both community resilience and relationships between residents and government agencies.

Phospholipid transfer proteins: a biological debut.

Eukaryotic cells contain a battery of cytosolic proteins that catalyse phospholipid movement in vitro. Current studies are now revealing some surprising aspects of the in vivo function of such proteins, and are also uncovering previously unsuspected relationships between secretory pathway function, intracellular phospholipid transport, phospholipid biosynthesis, and the dynamics of the actin cytoskeleton.

SAC1p is an integral membrane protein that influences the cellular requirement for phospholipid transfer protein function and inositol in yeast.

Mutations in the SAC1 gene exhibit allele-specific genetic interactions with yeast actin structural gene defects and effect a bypass of the cellular requirement for the yeast phosphatidylinositol/phosphatidylcholine transfer protein (SEC14p), a protein whose function is essential for sustained Golgi secretory function. We report that SAC1p is an integral membrane protein that localizes to the yeast Golgi complex and to the yeast ER, but does not exhibit a detectable association with the bulk of the yeast F-actin cytoskeleton. The data also indicate that the profound in vivo effects on Golgi secretory function and the organization of the actin cytoskeleton observed in sac1 mutants result from loss of SAC1p function. This cosuppression of actin and SEC14p defects is a unique feature of sac1 alleles as mutations in other SAC genes that result in a suppression of actin defects do not result in phenotypic suppression of SEC14p defects. Finally, we report that sac1 mutants also exhibit a specific inositol auxotrophy that is not exhibited by the other sac mutant strains. This sac1-associated inositol auxotrophy is not manifested by measurable defects in de novo inositol biosynthesis, nor is it the result of some obvious defect in the ability of sac1 mutants to utilize inositol for phosphatidylinositol biosynthesis. Thus, sac1 mutants represent a novel class of inositol auxotroph in that these mutants appear to require elevated levels of inositol for growth. On the basis of the collective data, we suggest that SAC1p dysfunction exerts its pleiotropic effects on yeast Golgi function, the organization of the actin cytoskeleton, and the cellular requirement for inositol, through altered metabolism of inositol glycerophospholipids.

A phosphatidylinositol transfer protein controls the phosphatidylcholine content of yeast Golgi membranes.

SEC14p is required for protein transport from the yeast Golgi complex. We describe a quantitative analysis of yeast bulk membrane and Golgi membrane phospholipid composition under conditions where Golgi secretory function has been uncoupled from its usual SEC14p requirement. The data demonstrate that SEC14p specifically functions to maintain a reduced phosphatidylcholine content in Golgi membranes and indicate that overproduction of SEC14p markedly reduces the apparent rate of phosphatidylcholine biosynthesis via the CDP-choline pathway in vivo. We suggest that SEC14p serves as a sensor of Golgi membrane phospholipid composition through which the activity of the CDP-choline pathway in Golgi membranes is regulated such that a phosphatidylcholine content that is compatible with the essential secretory function of these membranes is maintained.

Auditory neurophysiologic responses and discrimination deficits in children with learning problems.

Children with learning problems often cannot discriminate rapid acoustic changes that occur in speech. In this study of normal children and children with learning problems, impaired behavioral discrimination of a rapid speech change (/dalpha/versus/galpha/) was correlated with diminished magnitude of an electrophysiologic measure that is not dependent on attention or a voluntary response. The ability of children with learning problems to discriminate another rapid speech change (/balpha/versus/walpha/) also was reflected in the neurophysiology. These results indicate that some children's discrimination deficits originate in the auditory pathway before conscious perception and have implications for differential diagnosis and targeted therapeutic strategies for children with learning disabilities and attention disorders.

Decrease of D2 receptor binding but increase in D2-stimulated G-protein activation, dopamine transporter binding and behavioural sensitization in brains of mice treated with a chronic escalating dose 'binge' cocaine administration paradigm.

Understanding the neurobiology of the transition from initial drug use to excessive drug use has been a challenge in drug addiction. We examined the effect of chronic 'binge' escalating dose cocaine administration, which mimics human compulsive drug use, on behavioural responses and the dopaminergic system of mice and compared it with a chronic steady dose (3 x 15 mg/kg/day) 'binge' cocaine administration paradigm. Male C57BL/6J mice were injected with saline or cocaine in an escalating dose paradigm for 14 days. Locomotor and stereotypy activity were measured and quantitative autoradiographic mapping of D(1) and D(2) receptors, dopamine transporters and D(2)-stimulated [(35)S]GTPgammaS binding was performed in the brains of mice treated with this escalating and steady dose paradigm. An initial sensitization to the locomotor effects of cocaine followed by a dose-dependent increase in the duration of the locomotor effect of cocaine was observed in the escalating but not the steady dose paradigm. Sensitization to the stereotypy effect of cocaine and an increase in cocaine-induced stereotypy score was observed from 3 x 20 to 3 x 25 mg/kg/day cocaine. There was a significant decrease in D(2) receptor density, but an increase in D(2)-stimulated G-protein activity and dopamine transporter density in the striatum of cocaine-treated mice, which was not observed in our steady dose paradigm. Our results document that chronic 'binge' escalating dose cocaine treatment triggers profound behavioural and neurochemical changes in the dopaminergic system, which might underlie the transition from drug use to compulsive drug use associated with addiction, which is a process of escalation.

The Hierarchy of Proinflammatory Cytokines in Ocular Inflammation.

PURPOSE: The concept of tissue-dependent cytokine hierarchy has been demonstrated in a number of diseases, but it has not been investigated in ophthalmic diseases. Here, we evaluated the functional hierarchy of interleukin-1ß (IL-1ß), IL-6, IL-17A, and tumor necrosis factor (TNF) in the induction of ocular inflammation. MATERIALS AND METHODS: We delivered adeno-associated virus (AAV) vectors expressing IL-1ß, IL-6, IL-17A, or TNF intravitreally in naïve C57/BL6 mice and compared and contrasted the inflammatory effects in the eye 5 weeks after AAV-mediated gene transfer. We also used an in vitro human system to test the effect of cytokines on barrier function. RESULTS: We found that IL-1ß had the highest ability to initiate ocular inflammation. The continuous overexpression of IL-1ß resulted in a significant upregulation of additional proinflammatory mediators in the eye. Using scanning laser ophthalmoscope and optical coherence tomography imaging techniques, we showed that a low dose of AAVIL-1ß was sufficient and was as pathogenic as a high dose of TNF in inducing vascular leakage, retinal degeneration, and cellular infiltration. Furthermore, only a marginal increase in IL-1ß was enough to cause cellular infiltration, thus confirming the highly pathogenic nature of IL-1ß in the eye. Contrary to our expectation, IL-6 or IL-17A had minimal or no effect in the eye. To examine the clinical relevance of our findings, we used an impedance assay to show that IL-1ß alone or TNF alone was able to cause primary human retinal endothelial cell barrier dysfunction in vitro. Again, IL-6 alone or IL-17A alone had no effect on barrier function; however, in the presence of IL-1ß or TNF, IL-17A but not IL-6 may provide additive proinflammatory effects. CONCLUSIONS: Our studies demonstrate the existence of a functional hierarchy of proinflammatory cytokines in the eye, and we show that IL-1ß is the most pathogenic when it is continuously expressed in the eye.

The yeast BSD2-1 mutation influences both the requirement for phosphatidylinositol transfer protein function and derepression of phospholipid biosynthetic gene expression in yeast.

The BSD2-1 allele renders Saccharomyces cerevisiae independent of its normally essential requirement for phosphatidylinositol transfer protein (Sec14p) in the stimulation of Golgi secretory function and cell viability. We now report that BSD2-1 yeast mutants also exhibit yet another phenotype, an inositol auxotrophy. We demonstrate that the basis for this Ino- phenotype is the inability of BSD2-1 strains to derepress transcription of INO1, the structural gene for the enzyme that catalyzes the committed step in de novo inositol biosynthesis in yeast. This constitutive repression of INO1 expression is mediated through specific inactivation of Ino2p, a factor required for trans-activation of INO1 transcription, and we show that these transcriptional regulatory defects can be uncoupled from the "bypass Sec14p" phenotype of BSD2-1 strains. Finally, we present evidence that newly synthesized phosphatidylinositol is subject to accelerated turnover in BSD2-1 mutants and that prevention of this accelerated phosphatidyl-inositol turnover in turn negates suppression of Sec14p defects by BSD2-1. We propose that, in BSD2-1 strains, a product(s) generated by phosphatidylinositol turnover coordinately modulates the activities of both the Sec14p/Golgi pathway and the pathway through which transcription of phospholipid biosynthetic genes is derepressed.

Structure and partial genomic sequence of the human retinoblastoma susceptibility gene.

This report describes the genomic organization of the human retinoblastoma susceptibility locus. This gene spans approximately 200 kb of DNA within human chromosome 13, band q14. The previously determined cDNA sequence comprises 27 exons, ranging in size from 31 bp to 1873 bp, and 26 introns, ranging in size from 80 bp to 70,500 bp. We have mapped the positions of the exons and the positions of the recognition sites for six restriction endonucleases. We also present the sequence of 9.2% of the locus (18,335 bp), including approximately 200 bp of intron sequence immediately flanking each exon. This map of a wild-type allele will form the foundation for future studies of mutant, oncogenic alleles at this locus.

Novel rhodopsin mutations Gly114Val and Gln184Pro in dominant retinitis pigmentosa.

PURPOSE: To identify mutations in the rhodopsin gene in North American patients with autosomal dominant retinitis pigmentosa (ADRP) and to measure the proportion of cases with rhodopsin mutations. METHODS: Single-strand conformation polymorphism (SSCP) analysis and direct genomic sequencing were used to evaluate the coding region and intron splice sites of the rhodopsin gene for mutations in 91 unrelated patients. RESULTS: Nineteen patients heterozygously carried a missense change in the rhodopsin gene (six with Pro23His, two with Pro347Leu, and one each with Thr17Met, Phe45Leu, Gly51Arg, Gly89Asp, Gly114Val, Arg135Trp, Pro171Leu, Gln184Pro, Phe220Leu, Ser297Arg, and Pro347Thr). All these missense changes were previously reported as causes for ADRP except for Gly114Val, Gln184Pro, and Phe220Leu, which were evaluated further by examining the relatives of index patients. The Gly114Val and Gln184Pro alleles cosegregated with ADRP as expected if they were pathogenic. Phe220Leu did not, indicating that it is not a cause of ADRP. CONCLUSIONS: Summation of the results of cases in this study with those of 272 unrelated cases of ADRP previously evaluated by our group shows that 90 of 363 (25%) of cases were caused by rhodopsin mutations.

Clinical features and mutations in patients with dominant retinitis pigmentosa-1 (RP1).

PURPOSE: To survey patients with dominant retinitis pigmentosa (RP) for mutations in the RP1 gene to determine the spectrum of dominant mutations in this gene, to estimate the proportion of dominant RP caused by this gene, and to determine whether the clinical features of patients with RP1 mutations differ from features of those with rhodopsin mutations. METHODS: A set of 241 patients who did not have mutations in the rhodopsin gene (based on previous work) formed the basis for the study. Of these patients, 117 had also been previously evaluated and were found not to carry mutations in the RDS gene. The single-strand conformation polymorphism (SSCP) method was used to search for sequence variants, which were then directly sequenced. The relatives of selected patients were recruited for segregation analyses. Clinical evaluations of patients included a measurement of Snellen visual acuity, final dark adaptation thresholds, visual fields, and ERGs. Clinical data were compared with those obtained earlier from a study of 128 patients with dominant rhodopsin mutations. RESULTS: Of the 241 patients, all were screened for the most common RP1 mutation (Arg677Ter), and 10 patients were found to have this mutation. In addition, an evaluation of a subset of 189 patients in whom the entire coding sequence was evaluated revealed the following mutations: Gln679Ter (1 case), Gly723Ter (2 cases), Glu729(1-bp del) (1 case), Leu762(5-bp del) (2 cases), and Asn763(4-bp del) (1 case). All of these mutations cosegregated with RP in the families of the index patients. Nine missense mutations that were each found in six or fewer patients were encountered. The segregation of eight of these was evaluated in the respective patients' families, and only one segregated with dominant RP. This cosegregating missense change was in cis with the nonsense mutation Gln679Ter. Although patients with RP1 mutations had, on average, slightly better visual acuity than patients with rhodopsin mutations, there was no statistically significant difference in final dark-adaptation thresholds, visual field diameters, or cone electroretinogram (ERG) amplitudes. Comparably aged patients with RP1 mutations had visual function that varied by approximately two orders of magnitude, based on visual fields and ERG amplitudes. CONCLUSIONS: Dominant RP1 alleles typically have premature nonsense codons occurring in the last exon of the gene and would be expected to encode mutant proteins that are only approximately one third the size of the wild-type protein, suggesting that a dominant negative effect rather than haploinsufficiency is the mechanism leading to RP caused by RP1 mutations. On average, patients with RP1 mutations have slightly better visual acuity than patients with dominant rhodopsin mutations; otherwise, they have similarly severe disease. The wide range in severity among patients with RP1 mutations indicates that other genetic or environmental factors modulate the effect of the primary mutation.