Positional cloning of the gene for X-linked retinitis pigmentosa 3: homology with the guanine-nucleotide-exchange factor RCC1

The gene for retinitis pigmentosa 3 (RP3), the most frequent form of X- linked RP (XLRP), has been mapped previously to a chromosome interval of less than 1000 kbp between the DXS1110 marker and the OTC locus at Xp21.1-p11.4. Employing a novel technique, YAC Representation Hybridization (YRH)', we have recently identified a small XLRP associated microdeletion in this interval, as well as several putative exons including the 3' end of a gene that was truncated by the deletion. cDNA library screening and sequencing of a cosmid centromeric to the deletion has now enabled us to identify numerous additional exons and to detect several point mutations in patients with XLRP. The predicted gene product shows homology to RCC1, the guanine-nucleotide- exchange factor (GEF) of the Ras-like GTPase Ran. Our findings suggest that we have cloned the long-sought RP3 gene, and that it may encode the GEF of a retina-specific GTP-binding protein.      

Localization of a novel X-linked congenital stationary night blindness locus: close linkage to the RP3 type retinitis pigmentosa gene region

X-linked congenital stationary night blindness (CSNBX) is anon-progressive retinal disorder characterized by decreasedvisual acuity and loss of night vision. CSNBX Is clinicallyheterogeneous with respect to the involvement of retinal rodsand/or cones in the disease. in this study, we localize a newlocus for CSNBX to Xp21.1, thus providing evidence that CSNBXis also genetically heterogeneous. A clear correlation betweendifferent genotypes and phenotypes cannot be found yet. Thenew CSNBX gene described here is closely linked to the X-linkedretinitis pigmentosa type 3 gene region, which supports thehypothesis that there may be a functional relationship betweencongenital stationary night blindness and retinitis pigmentosa.     

A Locus for Autosomal Recessive Pseudoxanthoma Elasticum, with Penetrance of Vascular Symptoms in Carriers, Maps to Chromosome 16p13.1

Pseudoxanthoma elasticum (PXE) is a heritable systemic disorder characterized by calcification of the elastic fibers of the connective tissue. Symptoms are predominantly noted in the eye, the skin, and the cardiovascular system, resulting in visual loss, skin lesions, and life-threatening vascular disease. In this study we combined homozygosity mapping and genome scanning with 374 markers in affected individuals from a PXE family from a genetically isolated population in The Netherlands. Initial homozygosity in two or three patients was found with up to 20 markers, among which D16S292 located in 16p13.1. Upon refined and more extensive family screening of the latter region, close linkage without recombination was found with the marker D16S764 (Z_max=6.27). Despite clear autosomal recessive inheritance of the ocular symptoms in PXE, vascular symptoms appear in 40%–50% of the heterozygotes.     

Linkage analysis of anorexia and bulimia nervosa cohorts using selected behavioral phenotypes as quantitative traits or covariates.

To increase the likelihood of finding genetic variation conferring liability to eating disorders, we measured over 100 attributes thought to be related to liability to eating disorders on affected individuals from multiplex families and two cohorts: one recruited through a proband with anorexia nervosa (AN; AN cohort); the other recruited through a proband with bulimia nervosa (BN; BN cohort). By a multilayer decision process based on expert evaluation and statistical analysis, six traits were selected for linkage analysis (1): obsessionality (OBS), age at menarche (MENAR), and anxiety (ANX) for quantitative trait locus (QTL) linkage analysis; and lifetime minimum body mass index (BMI), concern over mistakes (CM), and food-related obsessions (OBF) for covariate-based linkage analysis. The BN cohort produced the largest linkage signals: for QTL linkage analysis, four suggestive signals: (for MENAR, at 10p13; for ANX, at 1q31.1, 4q35.2, and 8q13.1); for covariate-based linkage analyses, both significant and suggestive linkages (for BMI, one significant [4q21.1] and three suggestive [3p23, 10p13, 5p15.3]; for CM, two significant [16p13.3, 14q21.1] and three suggestive [4p15.33, 8q11.23, 10p11.21]; and for OBF, one significant [14q21.1] and five suggestive [4p16.1, 10p13.1, 8q11.23, 16p13.3, 18p11.31]). Results from the AN cohort were far less compelling: for QTL linkage analysis, two suggestive signals (for OBS at 6q21 and for ANX at 9p21.3); for covariate-based linkage analysis, five suggestive signals (for BMI at 4q13.1, for CM at 11p11.2 and 17q25.1, and for OBF at 17q25.1 and 15q26.2). Overlap between the two cohorts was minimal for substantial linkage signals.     

Haemodynamic Adjustments to Mental Stress in Normotensives and Subjects with Mildly Elevated Blood Pressure

Cardiac output, heart rate, stroke volume, pre-ejection period, total peripheral resistance, systolic and diastolic blood pressure, and oxygen consumption were monitored or derived in young men with mildly elevated casual blood pressures and unambiguously normotensive control subjects before, during, and after exposure to a mental arithmetic stress. Measurements were also taken while subjects underwent graded dynamic exercise. This permitted cardiac output-oxygen consumption regression equations to be calculated and, as a consequence, cardiac output during mental stress to be represented as additional cardiac output. Systolic and diastolic blood pressure were higher during all phases of the study in the mildly elevated blood pressure group. An overall groups effect during the mental stress phase of the experiment was observed for cardiac output and pre-ejection period, and the effect for stroke volume was close to significance. Significant Groups X Periods interactions were found for cardiac output and additional cardiac output, and the heart rate effect was nearly significant. Post-hoc comparisons here indicated that, in the main, group differences in these cardiac variables were more evident during the mental arithmetic stress than during the pre- and post-task baseline periods. Total peripheral resistance did not differ reliably between groups and the cardiac effects were specific to the mental stress phase of the study.     

Promotion of retroviral entry in the absence of envelope protein by chlorpromazine

Retrovirus packaging cell lines that express the Moloney murine leukemia virus gag, pol, and env genes and a retroviral vector genome can produce virus particles that are capable of transducing cells. Normally if the packaging cell line does not produce a functional viral fusion glycoprotein, such as the retroviral envelope protein or a foreign viral glycoprotein, then the viruses will be incapable of transducing cells. We have found that incubating envelope protein-deficient virus particles bound to cells with chlorpromazine leads to transduction. Chlorpromazine (CPZ) is a membrane-active reagent that is commonly used to induce the hemifusion to fusion transition when membrane fusion is mediated by partially defective viral glycoproteins. The concentration and pH dependence of the promotion of transduction by CPZ is consistent with a role for CPZ micelle formation in viral entry. These data indicate that caution is warranted when experiments concerning membrane fusion completion promoted by CPZ are analyzed.     

Family Belongingness Attenuates Entrapment and Buffers Its Association with Suicidal Ideation in a Sample of Dutch Sexual Minority Emerging Adults

Sexual minority emerging adults are more likely to engage in suicidal ideation than their heterosexual counterparts. Experiences of homophobic violence are associated with suicidal ideation. Yet, the specific mechanisms linking homophobic violence to suicidal ideation remain unclear. Entrapment and social belongingness were tested to determine their relevance for understanding the link between homophobic violence and suicidal ideation. A sample of sexual minority Dutch emerging adults (N?=?675; ages 18–29, M?=?21.93 years, SD?=?3.20) were recruited through online platforms and flyers. Homophobic violence was expected to be positively associated with suicidal ideation and entrapment. The association between homophobic violence and suicidal ideation was expected to be indirectly linked through entrapment. We explored whether various sources of social belongingness moderated the path between entrapment and suicidal ideation and whether those sources of social belongingness moderated the indirect effect of homophobic violence on suicidal ideation through entrapment. Results showed that homophobic violence and entrapment were positively associated with suicidal ideation and that family belongingness was negatively associated with suicidal ideation. Homophobic violence and suicidal ideation were not indirectly linked through entrapment. The interaction effect between entrapment and family belongingness was significant, suggesting that, on average, the effect of entrapment on suicidal ideation decreased when family belongingness was high. These results suggest that family belongingness may reduce the association between entrapment and suicidal ideation while adjusting for homophonic violence. Reducing entrapment and improving family belongingness may be useful targets for programs aimed at preventing suicidal ideation among sexual minority emerging adults.