BMP4 Activation and Secretion Are Negatively Regulated by an Intracellular Gremlin-BMP4 Interaction

Bone morphogenetic protein 4 (BMP4) is a potent growth factor that is involved in many important biological processes. Regulation of the level of secreted mature BMP4 determines the biological effects of BMP4 on cells in the local microenvironment. Previous studies suggested that Gremlin, a member of DAN family proteins, antagonizes BMP4 activity by sequestering extracellular BMP4. Herein, we report a novel intracellular regulatory mechanism by which Gremlin interacts with BMP4 precursor, prevents secretion of mature BMP4, and therefore inhibits BMP4 activity more efficiently. Furthermore, we also defined a 30-amino acid peptide sequence within the Gremlin DAN domain that is essential for BMP4 interaction. This novel Gremlin-mediated BMP4 posttranslational regulatory mechanism implies that the level of BMP4 mRNA expression does not truly reflect BMP4 activity when Gremlin and BMP4 are coexpressed within the same cell. Similar regulatory mechanisms may be utilized by other DAN family proteins

The Antiviral Action of Interferon Is Potentiated by Removal of the Conserved IRTAM Domain of the IFNAR1 Chain of the Interferon α/β Receptor: Effects on JAK-STAT Activation and Receptor Down-regulation

The first cloned chain (IFNAR1) of the human interferon-α (IFNα) receptor acts as a species-specific transducer for type I IFN action when transfected into heterologous mouse cells. Stably transfected mouse L929 cell lines expressing truncation mutants of the intracellular domain of the human IFNAR1 chain were tested for biological responses to human IFNα. Deletion of the intracellular domain resulted in a complete loss of sensitivity to the biological activity of human IFN but markedly increased IFNAR1 cell surface expression, demonstrating that the intracellular domain is required for biological function and contains a domain that negatively regulates its cell surface expression. Removal of the conserved membrane distal 16-amino-acid IRTAM (InterferonReceptorTyrosineActivationMotif) sequence: (1) increased sensitivity to IFNα's antiviral activity, (2) increased the rapid IFNα-dependent formation of STAT-containing DNA-binding complexes, (3) prolonged tyrosine phosphorylation kinetics of the JAK-STAT pathway, and (4) blocked the IFN-dependent down-regulation of the IFNAR1 chain. These results indicate that the IRTAM negatively regulates signaling events required for the induction of IFN's biological actions via regulating receptor down-regulation

Association of ADAM10 and CAMK2A Polymorphisms With Conduct Disorder: Evidence From Family-Based Studies

Twin and family studies have shown that genetic factors play a role in the development of conduct disorder (CD). The purpose of this study was to identify genetic variants associated with CD using a family-based association study. We used 4,720 single nucleotide polymorphisms (SNPs) from the Illumina Panel and 11,120 SNPs from the Affymetrix 10K GeneChips genotyped in 155 Caucasian nuclear families from Genetic Analysis Workshop (GAW) 14, a subset from the Collaborative Study on the Genetics of Alcoholism (COGA). 20 SNPs had suggestive associations with CD (p∈\u3c∈10-3), nine of which were located in known genes, including ADAM10 (rs383902, p=0.00036) and CAMK2A (rs2053053, p=0.00098). Our results were verified using the International Multi-Center ADHD Genetics Project (IMAGE) dataset. In conclusion, we identified several loci associated with CD. Especially, the two genes (ADAM10 and CAMK2A) have been reported to be associated with Alzheimer\u27s disease, bipolar disorder and depression. These findings may serve as a resource for replication in other populations

Polymorphisms in ABLIM1 Are Associated With Personality Traits and Alcohol Dependence.

Personality traits like novelty seeking (NS), harm avoidance (HA), and reward dependence (RD) are known to be moderately heritable (30-60%). These personality traits and their comorbidities, such as alcohol dependence (AD), may share genetic components. We examined 11,120 single nucleotide polymorphisms (SNPs) genotyped in 292 nuclear families from the Genetic Analysis Workshop 14, a subset from the Collaborative Study on the Genetics of Alcoholism (COGA). A family-based association analysis was performed using the FBAT program. NS, HA, and RD were treated as quantitative traits and AD as a binary trait. Based on a multivariate association test of three quantitative traits in FBAT, we observed 20 SNPs with p \u3c 10(-3). Interestingly, several genes (TESK2, TIPARP, THEMIS, ABLIM1, RFX4, STON2 and LILRA1) are associated with three personality traits with p \u3c 10(-3) using single trait analysis and AD. Especially, SNP rs727532 within ABLIM1 gene at 10q25 showed the most significant association (p = 6.4 × 10(-5)) in the multivariate test and strong associations with NS, HA, RD, and AD (p = 4.48 × 10(-4), 1.2 × 10(-5), 5.6 × 10(-5), 3.12 × 10(-4), respectively) in the COGA sample. In addition, the association of rs727532 with AD was confirmed in a replication study. This study reports some newly recognized associations between several genetic loci and both AD and three personality traits

Family-Based Association Analysis of Alcohol Dependence in the COGA Sample and Replication in the Australian Twin-Family Study

Family, twin, and adoption studies have indicated that genetic and environmental factors contribute to the development of alcohol dependence (AD). We conducted a low-density genome-wide association analysis to identify genetic variants influencing AD. We used 11,120 SNPs from the Affymetrix 10K Genechips genotyped in 116 Caucasian pedigrees (272 nuclear families) from Genetic Analysis Workshop 14, a subset from the Collaborative Study on the Genetics of Alcoholism (COGA). Family-based association analyses for AD were performed by the PBAT program for autosomal SNPs and by the FBAT program for X-chromosome SNPs. We identified 37 SNPs associated with AD (P \u3c 10 -3), thirteen of which were located in known genes. The most significant association with AD was observed with SNP rs1986644 (P = 8.51 × 10 -6) at 13q22 near EDNRB gene. The next best signal was at 1q41 in USH2A (rs532342, P = 1.07 × 10 -5) and the third region was at 3q25.31 in TIPARP (rs1367311, P = 2.31 × 10 -5). Furthermore, we found support for association of MAOA gene (P = 4.14 × 10 -4 for rs979606). Six of the 37 AD associated SNPs were confirmed to be associated with AD in Australian twin-family study sample (P \u3c 0.05). Interestingly, four SNPs in DSCAML1 at 11q23 reached the genome-wide significance (the top SNP is rs10892169 with P = 5.31 × 10 -9), while rs637547 in NKAIN2 at 6q21 showed strong association with AD (P = 5.11 × 10 -7) in the replication sample. These findings offer the potential for new insights into the pathogenesis of AD and will serve as a resource for replication in other populations to elucidate the potential role of these genetic variants in AD

Polymorphisms in Seizure 6-Like Gene Are Associated With Bipolar Disorder I: Evidence of Gene×gender Interaction

Background: Previous reports have suggested that there may be gene×gender interaction for bipolar disorder (BD)-associated genes/loci at 22q11-13. This study aimed to investigate the associations of SEZ6L genetic variants with bipolar disorder I (BD-I) and to examine gender-specific genetic associations. Methods: 605 BD-I Caucasian cases and 1034 controls were selected from the publicly available data of the Whole Genome Association Study of BD. To increase power, an additional 362 Caucasian controls were added to this study from the Genome-Wide Association Study of Schizophrenia. In total, 605 BD-I cases and 1396 controls (934 males and 1067 females) were available for genetic association analysis of 118 SNPs within the SEZ6L gene using PLINK software. Results: 16 SNPs showed significant gene x gender interactions influencing BD-I (P\u3c0.01). In addition, significant differences in the distribution of the alleles for these 16 SNPs were observed between the female BD-I patients and healthy controls (P\u3c0.015) but no significant associations were found for the male sample (P\u3e0.05). The SNP rs4822691 showed the strongest association with BD-I in the female sample (P=2.18×10-4) and the strongest gene×gender interaction in influencing BD-I (P=9.16×10 -5). Limitations: The findings of this study need to be replicated in independent samples. Conclusions: This is the first demonstration that genetic variants in the SEZ6L gene are associated with BD-I in female patients and provides additional compelling evidence for genetic variation at 22q11-13 that influences BD-I risk. The present findings highlight the gene x gender interactions modifying BD-I susceptibility

A Consensus Curriculum for Laboratory Management Training for Pathology Residents

Through the combined efforts of the American Pathology Foundation (APF), the American Society for Clinical Pathology (ASCP), and the Program Directors Section (PRODS) of the Association of Pathology Chairs (APC), a needs assessment was performed via a survey on the PRODS listserv, workshops at the APC/PRODS annual meetings in 2009 and 2010, and a Work Group of representatives of APF, ASCP, and PRODS. Residency program needs and resource constraints common to training pathology residents in practice and laboratory management were identified. In addition, a consensus curriculum for management training was created to serve as a resource for residency training program directors and others. The curriculum was converted into a wiki design tool for use by program directors, residents, and faculty