Tumor suppressor WWOX binds to ΔNp63α and sensitizes cancer cells to chemotherapy.

The WWOX tumor suppressor is a WW domain-containing protein. Its function in the cell has been shown to be mediated, in part, by interacting with its partners through its first WW (WW1) domain. Here, we demonstrated that WWOX via WW1 domain interacts with p53 homolog, ΔNp63α. This protein-protein interaction stabilizes ΔNp63α, through antagonizing function of the E3 ubiquitin ligase ITCH, inhibits nuclear translocation of ΔNp63α into the nucleus and suppresses ΔNp63α transactivation function. Additionally, we found that this functional crosstalk reverses cancer cells resistance to cisplatin, mediated by ΔNp63α, and consequently renders these cells more sensitive to undergo apoptosis. These findings suggest a functional crosstalk between WWOX and ΔNp63α in tumorigenesis.

Early development of New Zealand hapuku Polyprion oxygeneios eggs and larvae.

This study describes for the first time the normal development of New Zealand hapuku Polyprion oxygeneios embryos and larvae reared from fertilization to 11 days post-hatch (dph) at a constant temperature. Fertilized eggs were obtained from natural spawnings from communally reared captive wild broodstock. Eggs averaged 2 mm in diameter and had single or multiple oil globules. Embryos developed following the main fish embryological stages and required an average of 1859·50 degree hours post-fertilization (dhpf) to hatch. The newly hatched larvae (4·86 mm mean total length, L(T) ) were undifferentiated, with unpigmented eyes, a single and simple alimentary tube and a finfold that covered the entire body. Larvae relied on the energy from the yolk-sac reserves until 11 dph (7·33 mm mean L(T) ), when yolk-sac reabsorption was almost completed. Some of the major developmental stages from hatching to yolk-sac reabsorption were eye pigmentation (5 dph), upper jaw formation (7 dph), lower jaw formation (8 dph) and mouth opening (8-9 dph). By 9 dph, the digestive system consisted of pancreas, liver, primordial stomach, anterior and posterior gut; therefore, P. oxygeneios larvae would be capable of feeding on live prey. The developmental, morphological and histological data described constitutes essential baseline information on P. oxygeneios biology and normal development.

Support for association of HSPG2 with tardive dyskinesia in Caucasian populations.

Tardive dyskinesia (TD) is a severe adverse effect of chronic antipsychotic drug treatment. In addition to clinical risk factors, TD susceptibility is influenced by genetic predisposition. Recently, Syu et al. (2010) reported a genome-wide association screening of TD in Japanese schizophrenia patients. The best result was association of single-nucleotide polymorphism (SNP) rs2445142 in the HSPG2 (heparan sulfate proteoglycan 2) gene with TD. In the present study, we report a replication study of the five top Japanese TD-associated SNPs in two Caucasian TD samples. Applying logistic regression and controlling for relevant clinical risk factors, we were able to replicate the association of HSPG2 SNP rs2445142 with TD in a prospective study sample of 179 Americans of European origin by performing a secondary analysis of the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) genome-wide association study data set, and using a perfect proxy surrogate marker (rs878949; P = 0.039). An association of the 'G' risk allele of HSPG2 SNP rs2445142 with TD was also shown in a sample of Jewish Israeli schizophrenia patients (retrospective, cross-sectional design; P = 0.03). Although the associations were only nominally significant, the findings provide further support for the possible involvement of HSPG2 in susceptibility to TD.

Evidence for an interaction of schizophrenia susceptibility loci on chromosome 6q23.3 and 10q24.33-q26.13 in Arab Israeli families.

A genome scan for schizophrenia related loci in Arab Israeli families by Lerer et al. [Lerer et al. (2003); Mol Psychiatry 8:488-498] detected significant evidence for linkage at chromosome 6q23. Subsequent fine mapping [Levi et al. (2005); Eur J Hum Genet 13:763-771], association [Amann-Zalcenstein et al. (2006); Eur J Hum Genet 14:1111-1119] and replication studies [Ingason et al. (2007); Eur J Hum Genet 15:988-991] identified AHI1 as a putative susceptibility gene. The same genome scan revealed suggestive evidence for a schizophrenia susceptibility locus in the 10q23-26 region. Genes at these two loci may act independently in the pathogenesis of the disease in our homogeneous sample of Arab Israeli families or may interact with each other and with other factors in a common biological pathway. The purpose of our current study was to test the hypothesis of genetic interaction between these two loci and to identify the type of interaction between them. The initial stage of our study focused on the 10q23-q26 region which has not been explored further in our sample. The second stage of the study included a test for possible genetic interaction between the 6q23.3 locus and the refined 10q24.33-q26.13 locus. A final candidate region of 19.9 Mb between markers D10S222 (105.3 Mb) and D10S587 (125.2 Mb) was found on chromosome 10 by non-parametric and parametric linkage analyses. These linkage findings are consistent with previous reports in the same chromosomal region. Two-locus multipoint linkage analysis under three complex disease inheritance models (heterogeneity, multiplicative, and additive models) yielded a best maximum LOD score of 7.45 under the multiplicative model suggesting overlapping function of the 6q23.3 and 10q24.33-q26.13 loci.

Excitement and confusion on chromosome 6q: the challenges of neuropsychiatric genetics in microcosm.

The search for genes that are implicated in the pathogenesis of schizophrenia (SCZ), bipolar disorder (BPD) and other complex neuropsychiatric phenotypes has yielded a plethora of positive findings, but has also engendered a substantial degree of confusion. Exciting findings include positive linkage results in a number of chromosomal regions and the identification of several genes that have been associated with SCZ and to a lesser extent with BPD. Confusing aspects include the difference between studies in localization of linkage peaks in the same chromosomal regions, raising the possibility that these regions may harbor more than one gene, the fact that positive linkage findings as well as associated genes appear in several cases to be shared by more than one disorder, and the failure to identify thus far the precise pathogenic variants in associated genes. Recent findings of linkage and association studies on chromosome 6q illustrate the current status of neuropsychiatric genetics in intriguing microcosm. Positive findings from linkage and association studies are reviewed in order to identify approaches that may help to settle apparent contradictions and allow an interpretation of the results that may prove useful in application to findings from other chromosomal regions. Not only SCZ and BPD but also other psychiatric and neurological phenotypes are considered. Taking a topographic approach, we identify five foci of positive findings on chromosome 6q and suggest that each may harbor gene(s) that confer susceptibility to SCZ or BPD or may modify their onset or clinical course. We further suggest that in searching for these genes the possibility that they may be implicated in more than one disorder should be taken into account. We also discuss the potential contribution of rare genetic variants identified in homogeneous, isolated populations to the subsequent identification of common variants in the same gene that contribute to disease susceptibility in outbred populations.

Genome scan of Arab Israeli families maps a schizophrenia susceptibility gene to chromosome 6q23 and supports a locus at chromosome 10q24.

Schizophrenia is a complex neuropsychiatric disorder to which an as-yet-unknown number of genes contribute, interacting with each other and the environment. Linkage analyses have implicated several chromosomal regions as harboring schizophrenia susceptibility loci although rarely at levels commensurate with proposed thresholds for genome-wide significance. We systematically recruited Arab Israeli families multiply affected with schizophrenia from the catchment area of a Regional Mental Health Center. Clinical diagnoses were established by semistructured interviews and all other available sources of information under narrow, core and broad categories. Using 350 microsatellite markers, spaced at an average of 10.3 cM, we performed an autosomal scan in 155 subjects from 21 families. Linkage analysis employed affects only, multipoint, nonparametric (model-free) and also parametric (dominant and recessive) approaches. We detected significant evidence for a schizophrenia susceptibility gene at chromosome 6q23 with a nonparametric LOD score (NPL) of 4.60 (P=0.000004) under the broad diagnostic category and a parametric LOD score of 3.33 (dominant model). Under the core diagnostic category the NPL was 4.29 (P=0.00001) and the LOD score 4.16 (dominant model). We also detected suggestive evidence for linkage at chromosome 10q24 under the broad diagnostic category (NPL 3.24, P=0.0008; heterogeneity LOD score, dominant model 2.65, alpha=0.82). Additionally, NPL scores >2.0 were observed at chromosome 2q37, 4p15-16, 7p22, 9q21-22 and 14q11.1-11.2. The linkage we detected at chromosome 6q23 fulfills the criteria for genome-wide significance and is located approximately midway between loci suggested by a previous significant report at chromosome 6q25 and findings located more centromerically at 6q21-22.

Aggravation of food-related behavior in an adolescent with Prader-Willi syndrome treated with fluvoxamine and fluoxetine.

UNLABELLED: Prader-Willi Syndrome is a congenital multisystem disorder, characterized by a typical dysmorphism, mental retardation, hyperphagia due to insatiable appetite, and resultant morbid obesity. Psychiatric symptoms include obsessions and temper tantrums. METHOD: Pharmacotherapy is experimental with a few reports of successful fluoxetine treatment. RESULTS: We report an aggravation in the food-related symptoms and a consequent weight gain in an adolescent with Prader-Willi syndrome, who was treated with fluvoxamine and fluoxetine.