1. Mouse Nbeal2 Human disease models (by orthology) Mouse phenotype associations Nbeal2 Summary Human ortholog NBEAL2 Gene expression NameNeurobeachin-like 2 SynonymsKIAA0540 Function Probably involved in thrombopoiesis. Plays a role in the development or secretion of alpha-granules, that contain several growth factors important for platelet biogenesis. Domains and Repeats NameNeurobeachin-like 2 Synonyms1110014F23Rik MGI IdMGI:2448554 In homozygote Both sexes have the following phenotypic abnormalities: skeleton phenotype hematopoietic system phenotype Following phenotypic abnormalities occurred in males only immune system phenotype. Hematology | Mean platelet volume P = 0.0 Name Gray Platelet Syndrome In Disease Locus Yes Synonyms BLEEDING DISORDER, PLATELET-TYPE, 4; BDPLT4, PLATELET ALPHA-GRANULE DEFICIENCY OMIM Description The gray platelet syndrome (GPS) is a rare inherited disorder characterized by mild to moderate bleeding tendency, moderate thrombocytopenia, and a marked decrease or absence of platelet alpha-granules and of the proteins contained in alpha-granules. The platelets are enlarged, but not giant, and have a gray appearance on light microscopy of Wright-stained peripheral blood smears due to decreased granules. Many patients with gray platelet syndrome develop a stable myelofibrosis (summary by Nurden and Nurden, 2007). Disease Name In Locus MGI IMPC Disease Name: Gray Platelet Syndrome Source: OMIM:139090 In Disease Locus:Yes MGI:86.59IMPC: 61.96 Disease Name: Gray Platelet Syndrome Source: ORPHANET:721 In Disease Locus: Yes MGI:70.3IMPC: 55.27 Gray Platelet Syndrome Yes 86.59 61.96 Gray Platelet Syndrome Yes 70.355.27 NameNeurobeachin-like 2 SynonymsKIAA0540 Function Probably involved in thrombopoiesis. Plays a role in the development or secretion of alpha-granules, that contain several growth factors important for platelet biogenesis. Subcellular location Endoplasmic reticulum GO Molecular Functions phospholipid binding GO Cellular Components endomembrane system; endoplasmic reticulum; extrinsic component of membrane; membrane GO Biological processes blood coagulation; endosomal transport; megakaryocyte development; platelet alpha granule organization; platelet formation Protein Existence Evidence at the protein level Expression Expressed in megakaryocytes Interaction? Phenotype plateau transepithelial electrical resistance, low transepithelial electrical resistance, mid transepithelial electrical resistance Protein Existence Evidence at protein level NameNeurobeachin-like 2 Synonyms1110014F23Rik MGI IdMGI:2448554 Function (predicted by similarity to human NBEAL2) Subcellular Location Endoplasmic reticulum GO Cellular Components endomembrane system; endoplasmic reticulum; extrinsic component of membrane; membrane GO Biological Processes blood coagulation; endosomal transport; megakaryocyte development : MGI platelet alpha granule organization Source: MGI platelet formation Source: UniProtKB wound healing GO Molecular Function - phospholipid binding Protein Existence Evidence at transcript level Allelic structure Subcellular location Endoplasmic reticulum GO Molecular Functions phospholipid binding GO Cellular Components endomembrane system; endoplasmic reticulum; extrinsic component of membrane; membrane GO Biological processes blood coagulation; endosomal transport; megakaryocyte development; platelet alpha granule organization; platelet formation Protein Existence Evidence at the protein level Interactions NBEAL2 – glgX (two hybrid pooling approach) Allelic Structure Mouse phenotype association images Knockout Lethality Armadillo-type fold Concanavalin A-like lectin/glucanase domain PH-BEACH domain BEACH domain WD40/YVTN repeat-like-containing domain WD40 repeat There is one disease associated by orthology with this gene: - Gray Platelet Syndrome Greater colour saturation means higher expression. Please note that expression values are not directly comparable across experiments. FPKM/TPM (Transcriptomics) > 0.5 embryonic viable

2. Description NBEAL2 belongs to the BEACH (beige and CHS1) domain- containing protein family, which includes NBEAL1 (609816), neurobeachin (NBEA; 604889), CHS1 (LYST; 606897), and LRBA (606453). NBEAL2 is predicted to have a role in alpha-granule biogenesis in megakaryocytes (Gunay-Aygun et al., 2011; Albers et al., 2011; Kahr et al., 2011). Molecular Genetics Simultaneously and independently, Gunay-Aygun et al. (2011), Albers et al. (2011), and Kahr et al. (2011) identified biallelic mutations in the NBEAL2 gene in patients with gray platelet syndrome (GPS; 139090), a rare autosomal recessive disorder characterized by mild to moderate bleeding tendency, moderate thrombocytopenia, and a marked decrease or absence of platelet alpha-granules and of the proteins contained in alpha-granules... Animal Model Albers et al. (2011) found that knockout of zebrafish Nbeal2 via morpholino oligonucleotides resulted in spontaneous tail bleeding in 41% of embryos. Morpholino knockdown resulted in complete abrogation of thrombocytes, the zebrafish equivalent of platelets, whereas mature erythrocytes were not affected. Approved Drugs OMIM Potential disease models More images ChEMBL: Can also get a list of compounds that target the target Can also identify targets by sequence similarity, if information for a particular target is unavailable Potential human disease models predicted by phenotypic similarity Disease NameIn Locus Aicardi-Goutieres Syndrome 1Yes Metaphyseal Chondrodysplasia, Jansen TypeYes Bleeding Disorder, Platelet-Type, 15 Sebastian Syndrome Platelet Glycoprotein Iv Deficiency platelet volume -/- 0.0 thrombocytopenia -/- 1.89E-15 increased leukocyte cell number -/- 2.29E-8 decreased bone mineral density -/- 4.04E-6 decreased bone mineral content -/- 2.72E-5 Phenotype Zygosity Sex P-value Ensembl Genomic Context Chromosome 9: 110,166,766-111,067,174 Nbeal2 (with extra info from other genes for illustration) STRING Predicted Functional Partners Reactome Pathway inferred by orthology Or genomic context, or ChEMBL compounds list…. ? Or OMIM disease info (for orthologue associated diseases) OMIM Information ChEMBL Target Information tenovin-6 Mass : 454.62800 Formula : C25H34N4O2S Summation p53 causes G1 arrest by inducing the expression of a cell cycle inhibitor, p21 (El-Deiry et al, 1993; Harper et al, 1993; Xiong et al, 1993). P21 binds and inactivates Cyclin-Cdk complexes that mediate G1/S progression, resulting in lack of phosphorylation of Rb, E2F sequestration and cell cycle arrest at the G1/S transition. Mice with a homozygous deletion of p21 gene are deficient in their ability to undergo a G1/S arrest in response to DNA damage (Deng et al, 1995). Rhbdl1 rhomboid, veinlet-like 1 0.878 Brd9 bromodomain containing 9 0.649 Sqstm1 sequestosome 1 0.516 Tnfrsf1a tumor necrosis factor receptor superfamily, member 1a 0.494 Snx17 sorting nexin 17 0.473 Selp selectin, platelet 0.469 Gpr128 G protein-coupled receptor 0.457 Srsf9 serine/arginine-rich splicing factor 9 0.447 Shank3 SH3/ankyrin domain gene 3 0.442 Rabggta Rab geranylgeranyl transferase 0.416 Target associated bioactivities Component Description cGMP-specific 3',5'-cyclic phosphodiesterase Relationship single protein Target Relations ChEMBL IDPref Name CHEMBL23630663',5'-cyclic phosphodiesteraseCHEMBL2111400Phosphodiesterase 3 and 5 (PDE3 and PDE5) SELECTIVITY GROUP CHEMBL2095220Phosphodiesterases; PDE5 & PDE6SELECTIVITY GROUP CHEMBL2111340Phosphodiesterase 4 and 5 (PDE4 and PDE5)SELECTIVITY GROUP CHEMBL2097161Phosphodiesterase, PDE1/PDE5PROTEIN FAMILY CHEMBL2111470Phosphodiesterase 2 and 5 (PDE2 and PDE5)SELECTIVITY GROUP ChEMBL IDPref NameTarget Type CHEMBL23630663',5'-cyclic phosphodiesterase PROTEIN FAMILY CHEMBL2111400Phosphodiesterase 3 and 5 (PDE3 and PDE5) SELECTIVITY GROUP CHEMBL2095220Phosphodiesterases; PDE5 & PDE6 SELECTIVITY GROUP CHEMBL2111340Phosphodiesterase 4 and 5 (PDE4 and PDE5) SELECTIVITY GROUP CHEMBL2097161Phosphodiesterase, PDE1/PDE5 PROTEIN FAMILY CHEMBL2111470Phosphodiesterase 2 and 5 (PDE2 and PDE5) SELECTIVITY GROUP ChEMBL IDNameMechanism of Action CHEMBL1963681AVANAFILPhosphodiesterase 5A inhibitor CHEMBL1737SILDENAFIL CITRATEPhosphodiesterase 5A inhibitor CHEMBL779TADALAFILPhosphodiesterase 5A inhibitor CHEMBL1339VARDENAFIL HYDROCHLORIDE Phosphodiesterase 5A inhibitor Potential human disease models predicted by phenotypic similarity Disease NameIn LocusMGI IMPC Aicardi-Goutieres Syndrome 1Yes53.9345.85 Metaphyseal Chondrodysplasia, Jansen TypeYes37.644.54 Bleeding Disorder, Platelet-Type, 1568.5181.74 Sebastian Syndrome83.8179.74 Platelet Glycoprotein Iv Deficiency82.1876.75