Mouse chromosome 17 candidate modifier genes for thrombosis

Springer Science and Business Media LLC - Tập 21 - Trang 337-349 - 2010
Qila Sa1, Erika Hart1, Joseph H. Nadeau2, Jane L. Hoover-Plow1,3
1Departments of Cardiovascular Medicine and Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, USA
2Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, USA
3Department of Molecular Cardiology, NB50, Lerner Research Institute, Cleveland Clinic, Cleveland, USA

Tóm tắt

Two overlapping quantitative trait loci (QTLs) for clot stability, Hmtb8 and Hmtb9, were identified on mouse chromosome 17 in an F2 intercross derived from C57BL/6J (B6) and B6-Chr17A/J (B6-Chr17) mouse strains. The intervals were in synteny with a QTL for thrombotic susceptibility on chromosome 18 in a human study, and there were 23 homologs between mouse and human. The objective of this study was to determine whether any of these genes in the syntenic region are likely candidates as modifiers for clot stability. Seven genes, Twsg1, Zfp161, Dlgap1, Ralbp1, Myom1, Rab31, and Emilin2, of the 23 genes with single nucleotide polymorphisms (SNPs) in the mRNA-UTR had differential expression in B6 and A/J mice. Dlgap1, Ralbp1, Myom1, and Emilin2 also had nonsynonymous SNPs. In addition, two other genes had nonsynonymous SNPs, Lama1 and Ndc80. Of these nine candidate genes, Emilin2 was selected for further analysis since other EMILIN (Elastin Microfibril Interface Located Protein) proteins have known functions in vascular structure and coagulation. Differences were found between B6 and A/J mice in vessel wall architecture and EMILIN2 protein in plasma, carotid vessel wall, and thrombi formed after ferric chloride injury. In B6-Chr17A/J mice both clot stability and Emilin2 mRNA expression were higher compared to those in B6 and A/J mice, suggesting the exposure of epistatic interactions. Although other homologous genes in the QTL region cannot be ruled out as causative genes, further investigation of Emilin2 as a candidate gene for thrombosis susceptibility is warranted.

Tài liệu tham khảo

Alpy F, Jivkov I, Sorokin L, Klein A, Arnold C et al (2005) Generation of a conditionally null allele of the laminin alpha1 gene. Genesis 43:59–70 Amma LL, Goodyear R, Faris JS, Jones I, Ng L et al (2003) An emilin family extracellular matrix protein identified in the cochlear basilar membrane. Mol Cell Neurosci 23:460–472 Argraves WS, Greene LM, Cooley MA, Gallagher WM (2003) Fibulins: physiological and disease perspectives. EMBO Rep 4:1127–1131 Bouwman J, Spijker S, Schut D, Wachtler B, Ylstra B et al (2006) Reduced expression of neuropeptide genes in a genome-wide screen of a secretion-deficient mouse. J Neurochem 99:84–96 Braghetta P, Ferrari A, De Gemmis P, Zanetti M, Volpin D et al (2004) Overlapping, complementary and site-specific expression pattern of genes of the EMILIN/Multimerin family. Matrix Biol 22:549–556 Christian S, Ahorn H, Novatchkova M, Garin-Chesa P, Park JE et al (2001) Molecular cloning and characterization of EndoGlyx-1, an EMILIN-like multisubunit glycoprotein of vascular endothelium. J Biol Chem 276:48588–48595 Colombatti A, Doliana R, Bot S, Canton A, Mongiat M et al (2000) The EMILIN protein family. Matrix Biol 19:289–301 Cutler G, Marshall LA, Chin N, Baribault H, Kassner PD (2007) Significant gene content variation characterizes the genomes of inbred mouse strains. Genome Res 17:1743–1754 Diaz-Rodriguez E, Sotillo R, Schvartzman JM, Benezra R (2008) Hec1 overexpression hyperactivates the mitotic checkpoint and induces tumor formation in vivo. Proc Natl Acad Sci USA 105:16719–16724 Doliana R, Bot S, Mungiguerra G, Canton A, Cilli SP et al (2001) Isolation and characterization of EMILIN-2, a new component of the growing EMILINs family and a member of the EMI domain-containing superfamily. J Biol Chem 276:12003–12011 Ekblom P, Lonai P, Talts JF (2003) Expression and biological role of laminin-1. Matrix Biol 22:35–47 Ginsburg D (2005) Identifying novel genetic determinants of hemostatic balance. J Thromb Haemost 3:1561–1568 Glazier A, Nadeau JH (2002) Finding genes that underlie complex traits. Science 298:2345–2349 Gould DB, Phalan FC, Breedveld GJ, van Mil SE, Smith RS et al (2005) Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Science 308:1167–1171 Graubert TA, Cahan P, Edwin D, Selzer RR, Richmond TA et al (2007) A high-resolution map of segmental DNA copy number variation in the mouse genome. PLoS Genet 3:e3 Hasstedt SJ, Bovill EG, Callas PW, Long GL (1998) An unknown genetic defect increases venous thrombosis risk, through interaction with protein C deficiency. Am J Hum Genet 63:569–576 Hayward CP, Bainton DF, Smith JW, Horsewood P, Stead RH et al (1993) Multimerin is found in the alpha-granules of resting platelets and is synthesized by a megakaryocytic cell line. J Clin Invest 91:2630–2639 Hayward CP, Fuller N, Zheng S, Adam F, Jeimy SB et al (2004) Human platelets contain forms of factor V in disulfide-linkage with multimerin. Thromb Haemost 92:1349–1357 Henrichsen CN, Chaignat E, Reymond A (2009) Copy number variants, diseases and gene expression. Hum Mol Genet 18:R1–R8 Hoover-Plow J, Shchurin A, Hart E, Sha J, Hill AE et al (2006) Genetic background determines response to hemostasis and thrombosis. BMC Blood Disord 6:6 Lee TY, Huang HD, Hung JH, Huang HY, Yang YS et al (2006) dbPTM: an information repository of protein post-translational modification. Nucleic Acids Res 34:D622–D627 Lembertas AV, Perusse L, Chagnon YC, Fisler JS, Warden CH et al (1997) Identification of an obesity quantitative trait locus on mouse chromosome 2 and evidence of linkage to body fat and insulin on the human homologous region 20q. J Clin Invest 100:1240–1247 MacKenzie B, Wolff R, Lowe N, Billington CJ Jr, Peterson A et al (2009) Twisted gastrulation limits apoptosis in the distal region of the mandibular arch in mice. Dev Biol 328:13–23 Malfait F, Symoens S, Coucke P, Nunes L, De Almeida S (2006) Total absence of the alpha2(I) chain of collagen type I causes a rare form of Ehlers-Danlos syndrome with hypermobility and propensity to cardiac valvular problems. J Med Genet 43:e36 Marcucci R, Romano M (2008) Thrombopoietin and its splicing variants: structure and functions in thrombopoiesis and beyond. Biochim Biophys Acta 1782:427–432 Melnick M, Petryk A, Abichaker G, Witcher D, Person AD et al (2006) Embryonic salivary gland dysmorphogenesis in twisted gastrulation deficient mice. Arch Oral Biol 51:433–438 Milanetto M, Tiso N, Braghetta P, Volpin D, Argenton F et al (2008) Emilin genes are duplicated and dynamically expressed during zebrafish embryonic development. Dev Dyn 237:222–232 Milewicz DM, Urban Z, Boyd C (2000) Genetic disorders of the elastic fiber system. Matrix Biol 19:471–480 Nadeau JH, Singer JB, Matin A, Lander ES (2000) Analysing complex genetic traits with chromosome substitution strains. Nat Genet 24:221–225 Nguyen MM, Rivera C, Griep AE (2005) Localization of PDZ domain containing proteins Discs Large-1 and Scribble in the mouse eye. Mol Vis 11:1183–1199 Numoto M, Niwa O, Kaplan J, Wong KK, Merrell K et al (1993) Transcriptional repressor ZF5 identifies a new conserved domain in zinc finger proteins. Nucleic Acids Res 21:3767–3775 Prasad SV, Duan ZH, Gupta MK, Surampudi VS, Volinia S et al (2009) Unique microRNA profile in end-stage heart failure indicates alterations in specific cardiovascular signaling networks. J Biol Chem 284:27487–27499 Price MG, Gomer RH (1993) Skelemin, a cytoskeletal M-disc periphery protein, contains motifs of adhesion/recognition and intermediate filament proteins. J Biol Chem 268:21800–21810 Reheman A, Tasneem S, Ni H, Hayward CP (2010) Mice with deleted multimerin 1 and alpha-synuclein genes have impaired platelet adhesion and impaired thrombus formation that is corrected by multimerin 1. Thromb Res 125(5):e177–e183 Robinson PN, Godfrey M (2000) The molecular genetics of Marfan syndrome and related microfibrillopathies. J Med Genet 37:9–25 Rodriguez-Gabin AG, Yin X, Si Q, Larocca JN (2009) Transport of mannose-6-phosphate receptors from the trans-Golgi network to endosomes requires Rab31. Exp Cell Res 315:2215–2230 Sa Q, Hart E, Hill AE, Nadeau JH, Hoover-Plow JL (2008) Quantitative trait locus analysis for hemostasis and thrombosis. Mamm Genome 19:406–412 Sasahara A, Kasuya H, Akagawa H, Ujiie H, Kubo O et al (2007) Increased expression of ephrin A1 in brain arteriovenous malformation: DNA microarray analysis. Neurosurg Rev 30:299–305 Scavello GS Jr, Paluru PC, Zhou J, White PS, Rappaport EF et al (2005) Genomic structure and organization of the high grade Myopia-2 locus (MYP2) critical region: mutation screening of 9 positional candidate genes. Mol Vis 11:97–110 Shavit JA, Manichaikul A, Lemmerhirt HL, Broman KW, Ginsburg D (2009) Modifiers of von Willebrand factor identified by natural variation in inbred strains of mice. Blood 114:5368–5374 She X, Cheng Z, Zollner S, Church DM, Eichler EE (2008) Mouse segmental duplication and copy number variation. Nat Genet 40:909–914 Singer JB, Hill AE, Burrage LC, Olszens K, Song J et al (2004) Genetic dissection of complex traits with chromosome substitution strains of mice. Science 304:445–448 Singhal SS, Yadav S, Singhal J, Sahu M, Sehrawat A et al (2008) Diminished drug transport and augmented radiation sensitivity caused by loss of RLIP76. FEBS Lett 582:3408–3414 Sobek-Klocke I, Disque-Kochem C, Ronsiek M, Klocke R, Jockusch H et al (1997) The human gene ZFP161 on 18p11.21-pter encodes a putative c-myc repressor and is homologous to murine Zfp161 (Chr 17) and Zfp161-rs1 (X Chr). Genomics 43:156–164 Soria JM, Almasy L, Souto JC, Buil A, Martinez-Sanchez E et al (2003) A new locus on chromosome 18 that influences normal variation in activated protein C resistance phenotype and factor VIII activity and its relation to thrombosis susceptibility. Blood 101:163–167 Steiner F, Weber K, Furst DO (1999) M band proteins myomesin and skelemin are encoded by the same gene: analysis of its organization and expression. Genomics 56:78–89 Stenina OI, Topol EJ, Plow EF (2007) Thrombospondins, their polymorphisms, and cardiovascular disease. Arterioscler Thromb Vasc Biol 27:1886–1894 Sudbery I, Stalker J, Simpson JT, Keane T, Rust AG et al (2009) Deep short-read sequencing of chromosome 17 from the mouse strains A/J and CAST/Ei identifies significant germline variation and candidate genes that regulate liver triglyceride levels. Genome Biol 10:R112 Voetsch B, Loscalzo J (2004) Genetic determinants of arterial thrombosis. Arterioscler Thromb Vasc Biol 24:216–229 Wang X, Ishimori N, Korstanje R, Rollins J, Paigen B (2005) Identifying novel genes for atherosclerosis through mouse-human comparative genetics. Am J Hum Genet 77:1–15 Zacchigna L, Vecchione C, Notte A, Cordenonsi M, Dupont S et al (2006) Emilin1 links TGF-beta maturation to blood pressure homeostasis. Cell 124:929–942 Zanetti M, Braghetta P, Sabatelli P, Mura I, Doliana R et al (2004) EMILIN-1 deficiency induces elastogenesis and vascular cell defects. Mol Cell Biol 24:638–650 Zavolan M, van N Nimwegen E (2006) The types and prevalence of alternative splice forms. Curr Opin Struct Biol 16:362–367