The RCC1 superfamily: From genes, to function, to disease

Ouadah Hadjebi1, Eduard Casas-Terradellas1, Francesc R. Garcia-Gonzalo1, Jose Luis Rosa1
1Departament de Ciències Fisiològiques II, IDIBELL, Campus de Bellvitge, Universitat de Barcelona, E-08907, L'Hospitalet de Llobregat, Barcelona, Spain

Tài liệu tham khảo

Nishimoto, 1978, Premature of chromosome condensation in a ts DNA-mutant of BHK cells, Cell, 15, 475, 10.1016/0092-8674(78)90017-X Ohtsubo, 1987, Isolation and characterization of the active cDNA of the human cell cycle gene (RCC1) involved in the regulation of onset of chromosome condensation, Genes Dev., 1, 585, 10.1101/gad.1.6.585 Nishitani, 1991, Loss of RCC1, a nuclear DNA-binding protein, uncouples the completion of DNA replication from the activation of cdc2 protein kinase and mitosis, EMBO J., 10, 1555, 10.1002/j.1460-2075.1991.tb07675.x Rosa, 1996, p619, a giant protein related to the chromosome condensation regulator RCC1, stimulates guanine nucleotide exchange on ARF1 and Rab proteins, EMBO J., 15, 4262, 10.1002/j.1460-2075.1996.tb00801.x Garcia-Gonzalo, 2005, The HERC proteins: functional and evolutionary insights, Cell. Mol. Life Sci., 62, 1826, 10.1007/s00018-005-5119-y Hood, 2007, RCC1 isoforms differ in their affinity for chromatin, molecular interactions and regulation by phosphorylation, J. Cell Sci., 120, 3436, 10.1242/jcs.009092 Hochrainer, 2005, The human HERC family of ubiquitin ligases: novel members, genomic organization, expression profiling, and evolutionary aspects, Genomics, 85, 153, 10.1016/j.ygeno.2004.10.006 Uhlmann, 1999, DelGEF, an RCC1-related protein encoded by a gene on chromosome 11p14 critical for two forms of hereditary deafness, FEBS Lett., 460, 153, 10.1016/S0014-5793(99)01333-2 Shu, 2007, RPGR mutation analysis and disease: an update, Human Mutat., 28, 322, 10.1002/humu.20461 Santos, 2006, Alternative splicing in protein associated with Myc (Pam) influences its binding to c-Myc, J. Neurosci. Res., 83, 222, 10.1002/jnr.20723 Neidhardt, 2007, Identification and characterization of a novel RPGR isoform in human retina, Human Mutat., 28, 797, 10.1002/humu.20521 Kirschner, 1999, RPGR transcription studies in mouse and human tissues reveal a retina-specific isoform that is disrupted in a patient with X-linked retinitis pigmentosa, Hum. Mol. Genet., 8, 1571, 10.1093/hmg/8.8.1571 Hubbard, 2007, Ensembl 2007, Nucleic Acids Res., 35, D610, 10.1093/nar/gkl996 Mulder, 2007, New developments in the InterPro database, Nucleic Acids Res., 35, D224, 10.1093/nar/gkl841 Renault, 1998, The 1.7 A crystal structure of the regulator of chromosome condensation (RCC1) reveals a seven-bladed propeller, Nature, 392, 97, 10.1038/32204 Hulo, 2008, The 20  years of PROSITE, Nucleic Acids Res., 36, D245, 10.1093/nar/gkm977 Stevens, 2008, RCC1-like repeat proteins: a pangenomic, structurally diverse new superfamily of beta-propeller domains, Proteins, 70, 378, 10.1002/prot.21521 Bateman, 2002, The Pfam protein families database, Nucleic Acids Res., 30, 276, 10.1093/nar/30.1.276 Bateman, 2000, The Pfam protein families database, Nucleic Acids Res., 28, 263, 10.1093/nar/28.1.263 Ochman, 2000, Lateral gene transfer and the nature of bacterial innovation, Nature, 405, 299, 10.1038/35012500 Lim, 2001, Crystal structure and kinetic analysis of beta-lactamase inhibitor protein-II in complex with TEM-1 beta-lactamase, Nat. Struct. Biol., 8, 848, 10.1038/nsb1001-848 Renault, 1999, Crystallization and preliminary X-ray analysis of human RCC1, the regulator of chromosome condensation, Acta Crystallogr., D Biol. Crystallogr., 55, 272, 10.1107/S0907444998007768 Chen, 2007, N-terminal alpha-methylation of RCC1 is necessary for stable chromatin association and normal mitosis, Nat. Cell Biol., 9, 596, 10.1038/ncb1572 Hutchins, 2004, Phosphorylation regulates the dynamic interaction of RCC1 with chromosomes during mitosis, Curr. Biol., 14, 1099, 10.1016/j.cub.2004.05.021 Li, 2004, Phosphorylation of RCC1 in mitosis is essential for producing a high RanGTP concentration on chromosomes and for spindle assembly in mammalian cells, Genes Dev., 18, 512, 10.1101/gad.1177304 Friedrich, 2006, Nuclear localization signal and protein context both mediate importin alpha specificity of nuclear import substrates, Mol. Cell. Biol., 26, 8697, 10.1128/MCB.00708-06 Seino, 1992, DNA-binding domain of RCC1 protein is not essential for coupling mitosis with DNA replication, J. Cell Sci., 102, 393, 10.1242/jcs.102.3.393 Mollinari, 2003, The mammalian passenger protein TD-60 is an RCC1 family member with an essential role in prometaphase to metaphase progression, Dev. Cell, 5, 295, 10.1016/S1534-5807(03)00205-3 Moore, 2002, Targeting of RCC1 to chromosomes is required for proper mitotic spindle assembly in human cells, Curr. Biol., 12, 1442, 10.1016/S0960-9822(02)01076-X Martineau-Thuillier, 1998, Colocalization of TD-60 and INCENP throughout G2 and mitosis: evidence for their possible interaction in signalling cytokinesis, Chromosoma, 107, 461, 10.1007/s004120050330 Nemergut, 2001, Chromatin docking and exchange activity enhancement of RCC1 by histones H2A and H2B, Science, 292, 1540, 10.1126/science.292.5521.1540 Sjolinder, 2004, Characterisation of an evolutionary conserved protein interacting with the putative guanine nucleotide exchange factor DelGEF and modulating secretion, Exp. Cell Res., 294, 68, 10.1016/j.yexcr.2003.09.033 Sjolinder, 2002, DelGEF, a homologue of the Ran guanine nucleotide exchange factor RanGEF, binds to the exocyst component Sec5 and modulates secretion, FEBS Lett., 532, 211, 10.1016/S0014-5793(02)03677-3 Lehman, 1998, A very large protein with diverse functional motifs is deficient in rjs (runty, jerky, sterile) mice, Proc. Natl. Acad. Sci. U. S. A., 95, 9436, 10.1073/pnas.95.16.9436 Davies, 2004, Expression patterns of the novel imprinted genes Nap1l5 and Peg13 and their non-imprinted host genes in the adult mouse brain, Gene Expr. Patterns, 4, 741, 10.1016/j.modgep.2004.03.008 Mitsui, 1999, A novel human gene encoding HECT domain and RCC1-like repeats interacts with cyclins and is potentially regulated by the tumor suppressor proteins, Biochem. Biophys. Res. Commun., 266, 115, 10.1006/bbrc.1999.1777 Kroismayr, 2004, HERC5, a HECT E3 ubiquitin ligase tightly regulated in LPS activated endothelial cells, J. Cell Sci., 117, 4749, 10.1242/jcs.01338 Dastur, 2006, Herc5, an interferon-induced HECT E3 enzyme, is required for conjugation of ISG15 in human cells, J. Biol. Chem., 281, 4334, 10.1074/jbc.M512830200 Wong, 2006, HERC5 is an IFN-induced HECT-type E3 protein ligase that mediates type I IFN-induced ISGylation of protein targets, Proc. Natl. Acad. Sci. U. S. A., 103, 10735, 10.1073/pnas.0600397103 Takeuchi, 2006, Identification and Herc5-mediated ISGylation of novel target proteins, Biochem. Biophys. Res. Commun., 348, 473, 10.1016/j.bbrc.2006.07.076 Cruz, 2001, HERC3 binding to and regulation by ubiquitin, FEBS Lett., 488, 74, 10.1016/S0014-5793(00)02371-1 Garcia-Gonzalo, 2005, Requirement of phosphatidylinositol-4,5-bisphosphate for HERC1-mediated guanine nucleotide release from ARF proteins, FEBS Lett., 579, 343, 10.1016/j.febslet.2004.11.095 Garcia-Gonzalo, 2004, The giant protein HERC1 is recruited to aluminum fluoride-induced actin-rich surface protrusions in HeLa cells, FEBS Lett., 559, 77, 10.1016/S0014-5793(04)00030-4 Rosa, 1997, A giant protein that stimulates guanine nucleotide exchange on ARF1 and Rab proteins forms a cytosolic ternary complex with clathrin and Hsp70, Oncogene, 15, 1, 10.1038/sj.onc.1201170 Rodriguez, 2007, Disruption of the ubiquitin ligase HERC4 causes defects in spermatozoon maturation and impaired fertility, Dev. Biol., 312, 501, 10.1016/j.ydbio.2007.09.053 Liu, 2002, A defect in a novel Nek-family kinase causes cystic kidney disease in the mouse and in zebrafish, Development, 129, 5839, 10.1242/dev.00173 Tan, 2004, Nek9, a novel FACT-associated protein, modulates interphase progression, J. Biol. Chem., 279, 9321, 10.1074/jbc.M311477200 Roig, 2002, Nercc1, a mammalian NIMA-family kinase, binds the Ran GTPase and regulates mitotic progression, Genes Dev., 16, 1640, 10.1101/gad.972202 Pelka, 2007, Adenovirus E1A proteins direct subcellular redistribution of Nek9, a NimA-related kinase, J. Cell. Physiol., 212, 13, 10.1002/jcp.20983 Holland, 2002, Purification, cloning, and characterization of Nek8, a novel NIMA-related kinase, and its candidate substrate Bicd2, J. Biol. Chem., 277, 16229, 10.1074/jbc.M108662200 Mahjoub, 2005, NIMA-related kinases defective in murine models of polycystic kidney diseases localize to primary cilia and centrosomes, J. Am. Soc. Nephrol., 16, 3485, 10.1681/ASN.2005080824 Liu, 2001, Direct inhibition of Bruton's tyrosine kinase by IBtk, a Btk-binding protein, Nat. Immunol., 2, 939, 10.1038/ni1001-939 Shu, 2005, RPGR ORF15 isoform co-localizes with RPGRIP1 at centrioles and basal bodies and interacts with nucleophosmin, Hum. Mol. Genet., 14, 1183, 10.1093/hmg/ddi129 Hong, 2003, RPGR isoforms in photoreceptor connecting cilia and the transitional zone of motile cilia, Investig. Ophthalmol. Vis. Sci., 44, 2413, 10.1167/iovs.02-1206 Khanna, 2005, RPGR-ORF15, which is mutated in retinitis pigmentosa, associates with SMC1, SMC3, and microtubule transport proteins, J. Biol. Chem., 280, 33580, 10.1074/jbc.M505827200 Zhao, 2003, The retinitis pigmentosa GTPase regulator (RPGR)-interacting protein: subserving RPGR function and participating in disk morphogenesis, Proc. Natl. Acad. Sci. U. S. A., 100, 3965, 10.1073/pnas.0637349100 Yamanaka, 2003, Unstable mutants in the peripheral endosomal membrane component ALS2 cause early-onset motor neuron disease, Proc. Natl. Acad. Sci. U. S. A., 100, 16041, 10.1073/pnas.2635267100 Topp, 2004, Alsin is a Rab5 and Rac1 guanine nucleotide exchange factor, J. Biol. Chem., 279, 24612, 10.1074/jbc.M313504200 Kunita, 2007, The Rab5 activator ALS2/alsin acts as a novel Rac1 effector through Rac1-activated endocytosis, J. Biol. Chem., 282, 16599, 10.1074/jbc.M610682200 Guo, 1998, Identification of a large Myc-binding protein that contains RCC1-like repeats, Proc. Natl. Acad. Sci. U. S. A., 95, 9172, 10.1073/pnas.95.16.9172 Yang, 2002, Developmental expression of PAM (protein associated with MYC) in the rodent brain, Brain Res., 136, 35, 10.1016/S0165-3806(02)00311-5 Lewcock, 2007, The ubiquitin ligase Phr1 regulates axon outgrowth through modulation of microtubule dynamics, Neuron, 56, 604, 10.1016/j.neuron.2007.09.009 Murthy, 2004, Pam and its ortholog highwire interact with and may negatively regulate the TSC1.TSC2 complex, J. Biol. Chem., 279, 1351, 10.1074/jbc.M310208200 Bos, 2007, GEFs and GAPs: critical elements in the control of small G proteins, Cell, 129, 865, 10.1016/j.cell.2007.05.018 Riddick, 2005, A systems analysis of importin-{alpha}–{beta} mediated nuclear protein import, J. Cell Biol., 168, 1027, 10.1083/jcb.200409024 Ohtsubo, 1989, The RCC1 protein, a regulator for the onset of chromosome condensation locates in the nucleus and binds to DNA, J. Cell Biol., 109, 1389, 10.1083/jcb.109.4.1389 Bamba, 2002, The GTPase Ran regulates chromosome positioning and nuclear envelope assembly in vivo, Curr. Biol., 12, 503, 10.1016/S0960-9822(02)00741-8 Askjaer, 2002, Ran GTPase cycle and importins alpha and beta are essential for spindle formation and nuclear envelope assembly in living Caenorhabditis elegans embryos, Mol. Biol. Cell, 13, 4355, 10.1091/mbc.E02-06-0346 Aebi, 1990, A yeast mutant, PRP20, altered in mRNA metabolism and maintenance of the nuclear structure, is defective in a gene homologous to the human gene RCC1 which is involved in the control of chromosome condensation, Mol. Gen. Genet., 224, 72, 10.1007/BF00259453 Ohtsubo, 1991, Mutation of the hamster cell cycle gene RCC1 is complemented by the homologous genes of Drosophila and S. cerevisiae, EMBO J., 10, 1265, 10.1002/j.1460-2075.1991.tb08068.x Schlenstedt, 1995, The GTP-bound form of the yeast Ran/TC4 homologue blocks nuclear protein import and appearance of poly(A)+ RNA in the cytoplasm, Proc. Natl. Acad. Sci. U. S. A., 92, 225, 10.1073/pnas.92.1.225 Ryan, 2003, The Ran GTPase cycle is required for yeast nuclear pore complex assembly, J. Cell Biol., 160, 1041, 10.1083/jcb.200209116 Clement, 2006, The nuclear GTPase Gsp1p can affect proper telomeric function through the Sir4 protein in Saccharomyces cerevisiae, Mol. Microbiol., 62, 453, 10.1111/j.1365-2958.2006.05374.x Hirose, 2006, Loss of RanGEF/Pim1 activity abolishes the orchestration of Ran-mediated mitotic cellular events in S. pombe, Genes Cells, 11, 29, 10.1111/j.1365-2443.2005.00919.x Matsumoto, 1991, Premature initiation of mitosis in yeast lacking RCC1 or an interacting GTPase, Cell, 66, 347, 10.1016/0092-8674(91)90624-8 Dilworth, 2005, The mobile nucleoporin Nup2p and chromatin-bound Prp20p function in endogenous NPC-mediated transcriptional control, J. Cell Biol., 171, 955, 10.1083/jcb.200509061 Rosasco-Nitcher, 2008, Centromeric Aurora-B activation requires TD-60, microtubules, and substrate priming phosphorylation, Science, 319, 469, 10.1126/science.1148980 Scheffner, 2007, HECT E3s and human disease, BMC Biochem., 8, S6, 10.1186/1471-2091-8-S1-S6 Chong-Kopera, 2006, TSC1 stabilizes TSC2 by inhibiting the interaction between TSC2 and the HERC1 ubiquitin ligase, J. Biol. Chem., 281, 8313, 10.1074/jbc.C500451200 Schwarz, 1998, Characterization of human hect domain family members and their interaction with UbcH5 and UbcH7, J. Biol. Chem., 273, 12148, 10.1074/jbc.273.20.12148 Belham, 2003, A mitotic cascade of NIMA family kinases. Nercc1/Nek9 activates the Nek6 and Nek7 kinases, J. Biol. Chem., 278, 34897, 10.1074/jbc.M303663200 O'Connell, 2003, Never say never. The NIMA-related protein kinases in mitotic control, Trends Cell Biol., 13, 221, 10.1016/S0962-8924(03)00056-4 Nigg, 2001, Mitotic kinases as regulators of cell division and its checkpoints, Nat. Rev., Mol. Cell Biol., 2, 21, 10.1038/35048096 Smith, 2006, Development of polycystic kidney disease in juvenile cystic kidney mice: insights into pathogenesis, ciliary abnormalities, and common features with human disease, J. Am. Soc. Nephrol., 17, 2821, 10.1681/ASN.2006020136 Sohara, 2008, Nek8 regulates the expression and localization of polycystin-1 and polycystin-2, J. Am. Soc. Nephrol., 19, 469, 10.1681/ASN.2006090985 Hoogenraad, 2003, Bicaudal D induces selective dynein-mediated microtubule minus end-directed transport, EMBO J., 22, 6004, 10.1093/emboj/cdg592 Hadano, 2006, Mice deficient in the Rab5 guanine nucleotide exchange factor ALS2/alsin exhibit age-dependent neurological deficits and altered endosome trafficking, Hum. Mol. Genet., 15, 233, 10.1093/hmg/ddi440 Devon, 2006, Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities, Proc. Natl. Acad. Sci. U. S. A., 103, 9595, 10.1073/pnas.0510197103 Lai, 2006, Amyotrophic lateral sclerosis 2-deficiency leads to neuronal degeneration in amyotrophic lateral sclerosis through altered AMPA receptor trafficking, J. Neurosci., 26, 11798, 10.1523/JNEUROSCI.2084-06.2006 Boylan, 2000, Identification of a novel protein interacting with RPGR, Hum. Mol. Genet., 9, 2085, 10.1093/hmg/9.14.2085 Roepman, 2000, The retinitis pigmentosa GTPase regulator (RPGR) interacts with novel transport-like proteins in the outer segments of rod photoreceptors, Hum. Mol. Genet., 9, 2095, 10.1093/hmg/9.14.2095 Hong, 2001, Retinitis pigmentosa GTPase regulator (RPGRr)-interacting protein is stably associated with the photoreceptor ciliary axoneme and anchors RPGR to the connecting cilium, J. Biol. Chem., 276, 12091, 10.1074/jbc.M009351200 Hong, 2000, A retinitis pigmentosa GTPase regulator (RPGR)-deficient mouse model for X-linked retinitis pigmentosa (RP3), Proc. Natl. Acad. Sci. U. S. A., 97, 3649, 10.1073/pnas.97.7.3649 Linari, 1999, The retinitis pigmentosa GTPase regulator, RPGR, interacts with the delta subunit of rod cyclic GMP phosphodiesterase, Proc. Natl. Acad. Sci. U. S. A., 96, 1315, 10.1073/pnas.96.4.1315 Semov, 2002, Microarray analysis of E-box binding-related gene expression in young and replicatively senescent human fibroblasts, Anal. Biochem., 302, 38, 10.1006/abio.2001.5515 Scholich, 2001, Protein associated with Myc (PAM) is a potent inhibitor of adenylyl cyclases, J. Biol. Chem., 276, 47583, 10.1074/jbc.M107816200 Pierre, 2004, PAM mediates sustained inhibition of cAMP signaling by sphingosine-1-phosphate, EMBO J., 23, 3031, 10.1038/sj.emboj.7600321 Gao, 2005, Histidine residues 912 and 913 in protein associated with Myc are necessary for the inhibition of adenylyl cyclase activity, Mol. Pharmacol., 67, 42, 10.1124/mol.104.005355 Jiao, 2002, Identification of target messenger RNA substrates for the murine deleted in azoospermia-like RNA-binding protein, Biol. Reprod., 66, 475, 10.1095/biolreprod66.2.475 Collier, 2005, The DAZL family proteins are PABP-binding proteins that regulate translation in germ cells, EMBO J., 24, 2656, 10.1038/sj.emboj.7600738 Fulga, 2008, Synapses and growth cones on two sides of a highwire, Neuron, 57, 339, 10.1016/j.neuron.2008.01.016 Ehnert, 2004, Protein associated with Myc (PAM) is involved in spinal nociceptive processing, J. Neurochem., 88, 948, 10.1046/j.1471-4159.2003.02229.x Burgess, 2004, Evidence for a conserved function in synapse formation reveals Phr1 as a candidate gene for respiratory failure in newborn mice, Mol. Cell. Biol., 24, 1096, 10.1128/MCB.24.3.1096-1105.2004 D'Souza, 2005, Formation of the retinotectal projection requires Esrom, an ortholog of PAM (protein associated with Myc), Development, 132, 247, 10.1242/dev.01578 Le Guyader, 2005, Esrom, an ortholog of PAM (protein associated with c-myc), regulates pteridine synthesis in the zebrafish, Dev. Biol., 277, 378, 10.1016/j.ydbio.2004.09.029 Wan, 2000, Highwire regulates synaptic growth in Drosophila, Neuron, 26, 313, 10.1016/S0896-6273(00)81166-6 Wu, 2005, Highwire function at the Drosophila neuromuscular junction: spatial, structural, and temporal requirements, J. Neurosci., 25, 9557, 10.1523/JNEUROSCI.2532-05.2005 Zhen, 2000, Regulation of presynaptic terminal organization by C. elegans RPM-1, a putative guanine nucleotide exchanger with a RING-H2 finger domain, Neuron, 26, 331, 10.1016/S0896-6273(00)81167-8 Schaefer, 2000, rpm-1, a conserved neuronal gene that regulates targeting and synaptogenesis in C. elegans, Neuron, 26, 345, 10.1016/S0896-6273(00)81168-X DiAntonio, 2001, Ubiquitination-dependent mechanisms regulate synaptic growth and function, Nature, 412, 449, 10.1038/35086595 Abrams, 2008, Cellular and molecular determinants targeting the Caenorhabditis elegans PHR protein RPM-1 to perisynaptic regions, Dev. Dyn., 237, 630, 10.1002/dvdy.21446 Collins, 2006, Highwire restrains synaptic growth by attenuating a MAP kinase signal, Neuron, 51, 57, 10.1016/j.neuron.2006.05.026 Wu, 2007, DFsn collaborates with Highwire to down-regulate the Wallenda/DLK kinase and restrain synaptic terminal growth, Neural Develop., 2, 16, 10.1186/1749-8104-2-16 Liao, 2004, An SCF-like ubiquitin ligase complex that controls presynaptic differentiation, Nature, 430, 345, 10.1038/nature02647 Nakata, 2005, Regulation of a DLK-1 and p38 MAP kinase pathway by the ubiquitin ligase RPM-1 is required for presynaptic development, Cell, 120, 407, 10.1016/j.cell.2004.12.017 Grill, 2007, C. elegans RPM-1 regulates axon termination and synaptogenesis through the Rab GEF GLO-4 and the Rab GTPase GLO-1, Neuron, 55, 587, 10.1016/j.neuron.2007.07.009 McCabe, 2004, Highwire regulates presynaptic BMP signaling essential for synaptic growth, Neuron, 41, 891, 10.1016/S0896-6273(04)00073-X Hermann, 2005, Genetic analysis of lysosomal trafficking in Caenorhabditis elegans, Mol. Biol. Cell, 16, 3273, 10.1091/mbc.E05-01-0060 Ma, 2004, Lightoid and Claret: a rab GTPase and its putative guanine nucleotide exchange factor in biogenesis of Drosophila eye pigment granules, Proc. Natl. Acad. Sci. U. S. A., 101, 11652, 10.1073/pnas.0401926101 Heras, 2002, PARF-1: an Arabidopsis thaliana FYVE-domain protein displaying a novel eukaryotic domain structure and phosphoinositide affinity, J. Exp. Bot., 53, 565, 10.1093/jexbot/53.368.565 Kliebenstein, 2002, Arabidopsis UVR8 regulates ultraviolet-B signal transduction and tolerance and contains sequence similarity to human regulator of chromatin condensation 1, Plant Physiol., 130, 234, 10.1104/pp.005041 Brown, 2005, A UV-B-specific signaling component orchestrates plant UV protection, Proc. Natl. Acad. Sci. U. S. A., 102, 18225, 10.1073/pnas.0507187102 Kaiserli, 2007, UV-B promotes rapid nuclear translocation of the Arabidopsis UV-B specific signaling component UVR8 and activates its function in the nucleus, Plant Cell, 10.1105/tpc.107.053330 Gogendeau, 2005, Nd6p, a novel protein with RCC1-like domains involved in exocytosis in Paramecium tetraurelia, Eukaryot. Cell, 4, 2129, 10.1128/EC.4.12.2129-2139.2005 Hadano, 2001, A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2, Nat. Genet., 29, 166, 10.1038/ng1001-166 Yang, 2001, The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis, Nat. Genet., 29, 160, 10.1038/ng1001-160 Gros-Louis, 2006, Genetics of familial and sporadic amyotrophic lateral sclerosis, Biochim. Biophys. Acta, 1762, 956, 10.1016/j.bbadis.2006.01.004 Chandran, 2007, Alsin and the molecular pathways of amyotrophic lateral sclerosis, Mol. Neurobiol., 36, 224, 10.1007/s12035-007-0034-x Cai, 2005, Loss of ALS2 function is insufficient to trigger motor neuron degeneration in knock-out mice but predisposes neurons to oxidative stress, J. Neurosci., 25, 7567, 10.1523/JNEUROSCI.1645-05.2005 Deng, 2007, Distal axonopathy in an alsin-deficient mouse model, Hum. Mol. Genet., 16, 2911, 10.1093/hmg/ddm251 Kanekura, 2004, Alsin, the product of ALS2 gene, suppresses SOD1 mutant neurotoxicity through RhoGEF domain by interacting with SOD1 mutants, J. Biol. Chem., 279, 19247, 10.1074/jbc.M313236200 Kanekura, 2005, A Rac1/phosphatidylinositol 3-kinase/Akt3 anti-apoptotic pathway, triggered by AlsinLF, the product of the ALS2 gene, antagonizes Cu/Zn-superoxide dismutase (SOD1) mutant-induced motoneuronal cell death, J. Biol. Chem., 280, 4532, 10.1074/jbc.M410508200 Erie, 2007, Mice deficient in the ALS2 gene exhibit lymphopenia and abnormal hematopietic function, J. Neuroimmunol., 182, 226, 10.1016/j.jneuroim.2006.10.019 Provinciali, 1988, Immunity assessment in the early stages of amyotrophic lateral sclerosis: a study of virus antibodies and lymphocyte subsets, Acta Neurol. Scand., 78, 449, 10.1111/j.1600-0404.1988.tb03686.x Bowers, 2004, Nek8, a NIMA family kinase member, is overexpressed in primary human breast tumors, Gene, 328, 135, 10.1016/j.gene.2003.12.002 Torres, 2006, Mechanisms of disease: autosomal dominant and recessive polycystic kidney diseases, Nat. Clin. Prac., 2, 40, 10.1038/ncpneph0070 Trapp, 2008, Defects in ciliary localization of Nek8 is associated with cystogenesis, Pediatr. Nephrol. (Berlin, Germany), 23, 377, 10.1007/s00467-007-0692-y Natoli, 2008, Pkd1 and Nek8 mutations affect cell–cell adhesion and cilia in cysts formed in kidney organ cultures, Am. J. Physiol., 294, F73 Otto, 2008, NEK8 mutations affect ciliary and centrosomal localization and may cause nephronophthisis, J. Am. Soc. Nephrol., 19, 587, 10.1681/ASN.2007040490 Cai, 2008, Too much of a good thing: does Nek8 link polycystic kidney disease and nephronophthisis?, J. Am. Soc. Nephrol., 19, 418, 10.1681/ASN.2008010084 Walkowicz, 1999, Molecular characterization of radiation- and chemically induced mutations associated with neuromuscular tremors, runting, juvenile lethality, and sperm defects in jdf2 mice, Mamm. Genome, 10, 870, 10.1007/s003359901106 Ji, 1999, The ancestral gene for transcribed, low-copy repeats in the Prader–Willi/Angelman region encodes a large protein implicated in protein trafficking, which is deficient in mice with neuromuscular and spermiogenic abnormalities, Hum. Mol. Genet., 8, 533, 10.1093/hmg/8.3.533 Ji, 2000, Structure of the highly conserved HERC2 gene and of multiple partially duplicated paralogs in human, Genome Res., 10, 319, 10.1101/gr.10.3.319 Amos-Landgraf, 1999, Chromosome breakage in the Prader–Willi and Angelman syndromes involves recombination between large, transcribed repeats at proximal and distal breakpoints, Am. J. Hum. Genet., 65, 370, 10.1086/302510 Nicholls, 2001, Genome organization, function, and imprinting in Prader–Willi and Angelman syndromes, Annu. Rev. Genomics Hum. Genet., 2, 153, 10.1146/annurev.genom.2.1.153 Sturm, 2008, A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue–brown eye color, Am. J. Hum. Genet., 82, 424, 10.1016/j.ajhg.2007.11.005 Kayser, 2008, Three genome-wide association studies and a linkage analysis identify HERC2 as a human iris color gene, Am. J. Hum. Genet., 82, 411, 10.1016/j.ajhg.2007.10.003 Eiberg, 2008, Blue eye color in humans may be caused by a perfectly associated founder mutation in a regulatory element located within the HERC2 gene inhibiting OCA2 expression, Hum. Genet., 123, 177, 10.1007/s00439-007-0460-x Yuan, 2001, Influenza B virus NS1 protein inhibits conjugation of the interferon (IFN)-induced ubiquitin-like ISG15 protein, EMBO J., 20, 362, 10.1093/emboj/20.3.362 Krug, 2003, Intracellular warfare between human influenza viruses and human cells: the roles of the viral NS1 protein, Virology, 309, 181, 10.1016/S0042-6822(03)00119-3 Wang, 2003, Studies characterizing 60 kDa autoantibodies in subjects with schizophrenia, Biol. Psychiatry, 53, 361, 10.1016/S0006-3223(02)01972-8 Merla, 2002, Identification of additional transcripts in the Williams–Beuren syndrome critical region, Hum. Genet., 110, 429, 10.1007/s00439-002-0710-x Ouyang, 2002, Mutations in the alternatively spliced exons of USH1C cause non-syndromic recessive deafness, Hum. Genet., 111, 26, 10.1007/s00439-002-0736-0 Mabuchi, 2001, Cloning and characterization of CLLD6, CLLD7, and CLLD8, novel candidate genes for leukemogenesis at chromosome 13q14, a region commonly deleted in B-cell chronic lymphocytic leukemia, Cancer Res., 61, 2870 Mertens, 2002, Down-regulation of candidate tumor suppressor genes within chromosome band 13q14.3 is independent of the DNA methylation pattern in B-cell chronic lymphocytic leukemia, Blood, 99, 4116, 10.1182/blood.V99.11.4116 Solomou, 2003, 13q deletion in chronic lymphocytic leukemia: characterization of E4.5, a novel chromosome condensation regulator-like guanine nucleotide exchange factor, Leuk. Lymphoma, 44, 1579, 10.1080/1042819031000099670 Latil, 2003, Extensive analysis of the 13q14 region in human prostate tumors: DNA analysis and quantitative expression of genes lying in the interval of deletion, Prostate, 57, 39, 10.1002/pros.10272 Clamp, 2004, The Jalview Java alignment editor, Bioinformatics, 20, 426, 10.1093/bioinformatics/btg430 Thompson, 1994, CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice, Nucleic Acids Res., 22, 4673, 10.1093/nar/22.22.4673 Thompson, 1997, The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools, Nucleic Acids Res., 25, 4876, 10.1093/nar/25.24.4876