HGNC Research Articles

Dynamic Role of Postsynaptic Caspase-3 and BIRC4 in Zebra Finch Song-Response Habituation

Activation of the protease caspase-3 is commonly thought to cause apoptotic cell death. Here, we show that caspase-3 activity is regulated at postsynaptic sites in brain following stimuli associated with memory (neural activation and subsequent response habituation) instead of cell death. In the zebra finch auditory forebrain, the concentration of caspase-3 active sites increases briefly within minutes after exposure to tape-recorded birdsong. With confocal and immunoelectron microscopy, we localize the activated enzyme to dendritic spines. The activated caspase-3 protein is present even in unstimulated brain but bound to an endogenous inhibitor, BIRC4 (xIAP), suggesting a mechanism for rapid release and sequestering at specific synaptic sites. Caspase-3 activity is necessary to consolidate a persistent physiological trace of the song stimulus, as demonstrated using pharmacological interference and the zenk gene habituation assay. Thus, the brain appears to have adapted a core component of cell death machinery to serve a unique role in learning and memory.

An update of the S100 nomenclature

The plethora of names given to S100 proteins resulted in considerable confusion. Here we present the official and updated nomenclature of this protein family, approved by the HGNC (HUGO gene nomenclature committee) and ECS (European Calcium Society).

Babel's tower revisited: a universal resource for cross-referencing across annotation databases.

Annotation databases are widely used as public repositories of biological knowledge. However, most of these resources have been developed by independent groups which used different designs and different identifiers for the same biological entities. As we show in this article, incoherent name spaces between various databases represent a serious impediment to using the existing annotations at their full potential. Navigating between various such name spaces by mapping IDs from one database to another is a very important issue which is not properly addressed at the moment. We have developed a web-based resource, Onto-Translate (OT), which effectively addresses this problem. OT is able to map onto each other different types of biological entities from the following annotation databases: Swiss-Prot, TrEMBL, NREF, PIR, Gene Ontology, KEGG, Entrez Gene, GenBank, GenPept, IMAGE, RefSeq, UniGene, OMIM, PDB, Eukaryotic Promoter Database, HUGO Gene Nomenclature Committee and NetAffx. Currently, OT is able to perform 462 types of mappings between 29 different types of IDs from 17 databases concerning 53 organisms. Among these, over 300 types of translations and 15 types of IDs are not currently supported by any other tool or resource. On average, OT is able to correctly map between 96 and 99% of the biological entities provided as input. In terms of speed, sets of approximately 20 000 IDs can be translated in <30 s, in most cases. OT is a part of Onto-Tools, which is freely available at http://vortex.cs.wayne.edu/Projects.html

HCOP: a searchable database of human orthology predictions

The HUGO Gene Nomenclature Committee (HGNC) Comparison of Orthology Predictions (HCOP) search tool combines the human, mouse, rat and chicken orthology assertions made by PhIGs, HomoloGene, Ensembl, Inparanoid, Mouse Genome Informatics (MGI) and HGNC, enabling users to identify predicted ortholog pairs for a specified gene or genes. The HCOP resource provides a useful method to integrate, compare and access a variety of disparate sources of human orthology data. The HCOP search tool, data and documentation are available at http://www.gene.ucl.ac.uk/hcop.

PharmGKB Submission Update: VIII. PBAT Submission of Genetic Variation in VKORC1 to the PharmGKB Network

Category: genotype Project: Pharmacogenetics, Biomarkers, and Antithrombotic Therapy [Table 1][1] provides the HUGO Gene Nomenclature Committee (HGNC) symbol, PharmGKB submission URL, submission date, and release date. [Table 2][2] provides the HGNC symbol, HGNC name, synonym, GenBank accession

PharmGKB Submission Update: VII. PAT Submissions of Genetic Variation in KCND3 to the PharmGKB Network

Category: genotype Project: Pharmacogenetics of Arrhythmia Therapy [Table 1][1] provides the HUGO Gene Nomenclature Committee (HGNC) symbol, PharmGKB submission URLs, submission dates, and release dates. [Table 2][2] provides the HGNC symbol, HGNC names, synonyms, GenBank accession number, and

No Association between Polymorphisms in CYP2E1, GSTM1, NAT1, NAT2 and the Risk of Gastric Adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition

No association between polymorphisms in CYP2E1, GSTM1, NAT1, NAT2 and the risk of gastric adenocarcinoma in the European prospective investigation into cancer and nutrition.

KLK31P is a novel androgen regulated and transcribed pseudogene of kallikreins that is expressed at lower levels in prostate cancer cells than in normal prostate cells

Fifteen human tissue kallikrein (KLK) genes have been identified as a cluster on chromosome 19. KLK expression is associated with various human diseases including cancers. Noncoding RNAs such as PCA3/DD3 and PCGEM1 have been identified in prostate cancer cells. Using massively parallel signature sequencing (MPSS) technology, RT-PCR, and 5' rapid amplification of cDNA ends (RACE), we identified and cloned a novel gene that maps to the KLK locus. We have characterized this gene, named as KLK31P by the HUGO Gene Nomenclature Committee, as an unprocessed KLK pseudogene. It contains five exons, two of which are KLK-derived while the rest are "exonized" interspersed repeats. KLK31P is expressed abundantly in prostate tissues and is androgen regulated. KLK31P is expressed at lower levels in localized and metastatic prostate cancer cells than in normal prostate cells. KLK31P is a novel androgen regulated and transcribed pseudogene of kallikreins that may play a role in prostate carcinogenesis or maintenance.

PharmGKB Submission Update: VI. PMT Submissions of Genetic Variations in Neurotransmitter Transporters (SLC6, SLC17, and SLC18) to the PharmGKB Network

Category: genotype Project: Pharmacogenetics of Membrane Transporters [Table 1][1] provides HUGO Gene Nomenclature Committee (HGNC) symbols, PharmGKB submission URLs, submission dates, and release dates. [Table 2][2] provides HGNC symbols, HGNC names, synonyms, GenBank accession numbers, and locus

PharmGKB Submission Update: IV. PMT Submissions of Genetic Variations in ATP-Binding Cassette Transporters to the PharmGKB Network

Category: genotype Project: Pharmacogenetics of Membrane Transporters [Table 1][1] provides HUGO Gene Nomenclature Committee (HGNC) symbols, PharmGKB submission URLs, submission dates, and release dates. [Table 2][2] provides HGNC symbols, HGNC names, synonyms, GenBank accession numbers, and locus

PharmGKB Submission Update: V. PMT Submissions of Genetic Variation in SLC22 Family Transporters

Category: genotype Project: Pharmacogenetics of Membrane Transporters [Table 1][1] provides HUGO Gene Nomenclature Committee (HGNC) symbols, PharmGKB submission URLs, submission dates, and release dates. [Table 2][2] provides HGNC symbols, HGNC names, synonyms, GenBank accession numbers, and locus

High expression of FMNL1 protein in T non-Hodgkin's lymphomas

We recently cloned a novel Formin-family human gene, denominated human leukocyte formin and posteriorly named as FMNL1 by the HUGO Gene Nomenclature Committee. This gene is overexpressed in lymphoid malignances and is found associated with Akt. Here, we describe the expression of the FMNL1 protein in 54 frozen biopsies of non-Hodgkin's lymphoma (NHL) patients and five reactive lymph nodes. Western blot analysis revealed expression of FMNL1 in all samples studied, although the highest expression was in T-cell NHL ( P < 0.05).

The HUGO Gene Nomenclature Database, 2006 updates

The HUGO Gene Nomenclature Committee (HGNC) aims to give every human gene a unique and ideally meaningful name and symbol. The HGNC database, previously known as Genew, contains over 22 000 public records with approved human gene nomenclature and associated information. The database has undergone major improvements throughout the last year, is publicly available for online searching at and has a new custom downloads interface at .

264 IDENTIFICATION OF THE PREDOMINANT TRANSCRIPT IN BOVINE OOCYTES, IN VITRO-DERIVED BLASTOCYSTS, AND IN NUCLEAR TRANSFER BLASTOCYSTS

Identification of transcripts produced during bovine embryogenesis is the first step in describing the normal developmental program. To that end, mRNA was isolated from in vitro-matured metaphase II oocytes (MPII), in vitro-produced 2-cell-stage (2-Cell), in vitro-produced precompact morula-stage (PCM), in vitro-produced blastocyst-stage (BL), and in vitro-produced nuclear transfer blastocyst-stage (NTBL) embryos. The mRNA was isolated by using Dynabeads® (Dynal, Inc., Lake Success, NY, USA), and amplified by using the SMART system. PCR products were purified and ligated into pSPORT1 and electroporated into E. coli. Random clones were selected for DNA sequencing. Sequence data were evaluated for quality and clustered by sequence similarity with sequences generated from a larger expressed sequence tag (EST) project (http://genome.rnet.missouri.edu/Bovine/) by using the tlcluster program from the University of Iowa. Sequences over 100 bp in length with average Phred scores of over 20 for the entire sequence were submitted to GenBank (NIH genetic sequence database). Sequences were compared to the bovine TIGR (The Institute for Genomic Research) and human databases to gather annotation. The best comparison is listed below by using the HUGO Gene Nomenclature Committee standards (http://www.gene.ucl.ac.uk/nomenclature/) when possible. The number of unique clusters, i.e. no match in GenBank, was 53, 120, 109, 115, and 135, for MPII, 2-Cell, PCM, BL, and NTBL, respectively. The total number of clusters per tissue ranged from 224 to 992. The percent of clusters (number of clusters per total number of ESTs) per library was 12% (224/1762), 42% (746/1771), 48% (819/1715), 49% (900/1818) and 53% (992/1876) for MPII, 2-Cell, PCM, BL, and NTBL, respectively. Either the quality of the MPII library was lower or the complexity of the MPII mRNA was less than mRNA in the other tissues. Examples of mRNA that were in different abundance are shown in Table 1. Clearly, as in other species, there are significant changes in mRNA abundance during early embryogenesis. Furthermore, NTBL embryos, even though they are morphologically similar to BL, possess a population of mRNA that is distinct from that in BL. Table 1. Comparison of mRNA Abundance During Bovine Embryogenesis This work was funded by the USDA NRI 2003–35205–12812 and Food for the 21st Century.

A revised nomenclature for mammalian acyl-CoA thioesterases/hydrolases

Acyl-CoA thioesterases, also known as acyl-CoA hydrolases, are a group of enzymes that hydrolyze CoA esters such as acyl-CoAs (saturated, unsaturated, branched-chain), bile acid-CoAs, CoA esters of prostaglandins, etc., to the corresponding free acid and CoA. However, there is significant confusion regarding the nomenclature of these genes. In agreement with the HUGO Gene Nomenclature Committee and the Mouse Genomic Nomenclature Committee, a revised nomenclature for mammalian acyl-CoA thioesterases/hydrolases has been suggested for the 12 member family. The family root symbol is ACOT, with human genes named ACOT1-ACOT12, and rat and mouse genes named Acot1-Acot12. Several of the ACOT genes are the result of splicing events, and these splice variants are cataloged.

Generetriever: Software to Extract All Genes and Transcripts in Between Two Genetic Markers to Assist Design of Human Custom Microarrays

180 BioTechniques Vol. 39, No. 2 (2005) Identifying the genes that are responsible for human genetic disorders with complex inheritance patterns (e.g., multigenic diseases) has proven to be more difficult than anticipated. Indeed, when the mode of inheritance is unknown, classical parametric linkage studies are not relevant. Nonparametric linkage analysis can help approximate the candidate loci, but this type of analysis often leads to the identification of large intervals (10–20 cM) that may contain hundreds of genes, thus rendering the candidate gene approach rather tedious (1). Adding an expression screening may significantly reduce the number of candidate genes. Microarray expression studies of the genes located within such genetic intervals should be performed on relevant tissues (2). The design of a custom microrarray containing probes of all the genes located in the intervals of interest is required to carry out such experiments. Designing such microarrays involves gathering much additional information concerning these genes, in particular, name, transcript accession numbers, or nucleotide sequences. Collecting these data manually is time-consuming and very error-prone. GeneRetriever is a Perl-based data mining tool developed to automate, accelerate, and secure the process of locally retrieving user-chosen comprehensive information about human genes or transcripts located between two genetic markers. As annotation strategies are specific for each database, we implemented a database parameter entry that allows collection of data from either the National Center for Biotechnology Information (NCBI; www.ncbi.nlm.nih. gov) or Ensembl (www.ensembl.org) databases (3,4). Then, several options make it possible to define which data should be included in the returned gene/transcript table. These options are clustered into three parts: (i) genespecific data; (ii) transcript-specific data; and (iii) expression analysis data. Gene-specific options include database (either NCBI or Ensembl) identifier, Hugo Gene Nomenclature Committee symbol (5), gene description, DNA strand (plus or minus), type of gene (known or predicted), cytogenetic localization, summary of functional annotations, Entrez Gene identifier (6), web address of either NCBI or Ensembl gene page, and the number of transcript variants. Additional transcript information is optionally available, such as Ensembl transcript or RefSeq accession numbers. Structural data, including transcript size, number of exons, and size of the longest exon, can also be added to the query. These data may be useful when working with predicted genes; for instance, the relevance of predicted genes composed of one single exon of <100 bp can be questioned. Nucleotide sequences can also be gathered; in addition, the retrieved size of the 3′ end of transcript sequences can be userdefined in order to facilitate the design of transcript-specific oligonucleotides for microarray spotting. Since GeneRetriever was developed to help the design of a custom gene expression study, the list of genes can be directly linked either to the available BENCHMARKS

Molecular Cloning and Characterization of Three Novel Lysozyme-Like Genes, Predominantly Expressed in the Male Reproductive System of Humans, Belonging to the C-Type Lysozyme/Alpha-Lactalbumin Family

Lysozymes, especially c-type lysozymes, are well-recognized bacteriolytic factors widely distributed in the animal kingdom and play a mainly protective role in host defense. The relatives of c-type lysozymes, alpha-lactalbumins, however, are only found in mammalian milk and possess a distinct biological function. These two proteins, having similar amino acid sequences, gene structure, and dimensional conformation, belong to the c-type lysozyme/alpha-lactalbumin family. Using human lysozyme as an information probe, we cloned four human cDNAs encoding homologues of human lysozyme; these were named LYZL2, LYZL4, LYZL6, and SPACA3 by the HUGO Gene Nomenclature Committee. Of these four, SPACA3 has been reported to code an intra-acrosomal sperm protein SLLP1. To our knowledge, the other three are reported here for the first time. Using Northern blot hybridization, including 16 different human tissues, we found that these four lysozyme-like genes were all highly expressed in the testis/epididymis. Further analysis of one, LYZL4, by in situ hybridization revealed that its mRNA was only detected in the epithelium of human epididymis, most abundantly in the caput, suggesting that LYZL4 plays a physiological role in male reproduction. By sequence analysis, we found that two essential catalytic residues of the human lysozyme were conserved in LYZL2 and LYZL6, whereas one site in LYZL4 and two sites in SPACA3 were replaced. The LYZL2, LYZL4, LYZL6, and SPACA3 genes were mapped to human chromosome 10p11.23, 3p21.33, 17q11.2, and 17q12, respectively, and displayed a similar genomic structure. Our data suggest that these four lysozyme-like genes, which have arisen from a common progenitor gene, play a major role in human reproduction.

Characterization of a Novel GTPase-activating Protein Associated with Focal Adhesions and the Actin Cytoskeleton

In the present study we characterize a novel RhoGAP protein (RC-GAP72) that interacts with actin stress fibers, focal adhesions, and cell-cell adherens junctions via its 185-amino acid C-terminal region. Overexpression of RC-GAP72 in fibroblasts induces cell rounding with partial or complete disruption of actin stress fibers and formation of membrane ruffles, lamellipodia, and filopodia. RC-GAP72 mutant truncated downstream of the GTPase-activating protein (GAP) domain retains the ability to stimulate membrane protrusions but fails to affect stress fiber integrity or induce cell retraction. A mutant protein consisting of the C terminus of RC-GAP72 and lacking the GAP domain does not exert any visible effect on cellular morphology. Inactivation of the GAP domain by a point mutation does not abolish the effect of RC-GAP72 on actin stress fibers but moderates its capability to induce membrane protrusions. Our data imply that the cytoskeletal localization of RC-GAP72 and its interaction with GTPases are essential for its effect on the integrity of actin stress fibers, whereas the induction of lamellipodia and filopodia depends on the activity of the GAP domain irrespective of binding to the actin cytoskeleton. We propose that RC-GAP72 affects cellular morphology by targeting activated Cdc42 and Rac1 GTPases to specific subcellular sites, triggering local morphological changes. The overall physiological functions of RC-GAP72 are presently unknown, yet our data suggest that RC-GAP72 plays a role in regulating cell morphology and cytoskeletal organization.

Systematic analysis and nomenclature of mammalian F-box proteins

Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA; Department of Pathology, New York University School of Medicine, New York, New York 10016, USA; HUGO Gene Nomenclature Committee, Department of Biology, University College London, London, NW1 2HE, United Kingdom; Partners Center for Genetics and Genomics, Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA

Corrections

In the article by N. Donato et al., titled “Imatinib Mesylate Resistance Through BCR-ABL Independence in Chronic Myelogenous Leukemia,” which appeared in the January 15, 2004 issue of Cancer Research (pp. 672–677), Bharat B. Aggarwal’s middle initial was omitted and Shishir Shishodia’s name was misspelled. The correct author list is as follows: Nicholas J. Donato, Ji Y. Wu, Jonathan Stapley, Hui Lin, Ralph Arlinghaus, Bharat B. Aggarwal, Shishir Shishodia, Maher Albitar, Kimberly Hayes, Hagop Kantarjian, and Moshe Talpaz.In the article by G. Akiri et al., titled “Lysyl Oxidase-Related Protein-1 Promotes Tumor Fibrosis and Tumor Progression in Vivo,” which appeared in the April 1, 2003 issue of Cancer Research (pp. 1657–1666), the nomenclature used for members of the lysyl oxidase gene family did not include the gene symbols currently recognized and approved by the HUGO Gene Nomenclature Committee and Mouse Genome Informatics database. As has been reported in recent reviews (2–4), the human lysyl oxidase gene family members are referred to as LOX or LO, LOXL or LOXL1, LOXL2, LOXL3, and LOXL4.Akiri and colleagues acknowledge that when preparing their manuscript they were aware that there were two different nomenclatures for the lysyl oxidases, as discussed in their introduction, but they chose the one not approved, as they were unaware that an official nomenclature had been adopted by the HUGO Nomenclature Committee.We would like to thank Drs. Katalin Csiszar and Sheri F. T. Fong, of the John A. Burns School of Medicine and the Cancer Research Center of Hawaii, University of Hawaii, Honolulu, HI, for bringing this nomenclature to the attention of Cancer Research readers.