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Lars Allan Larsen

Lars Allan Larsen

Professor, Centre vice-director / Professor

Functional genomics of human cardiac development and disease

Congenital heart disease (CHD) represent the most common group of inborn malformations, with an incidence of almost 1% in the population. The aetiology of CHD is complex but with a significant genetic component. Large families with CHD are very rare, thus classical genetic approaches are generally not useful for identification of disease genes and consequently the present number of identified human genes involved in cardiac development and CHD is small. Our research is focused on investigating the genetic aspects of human cardiac development and congenital heart disease. We explore different genomic strategies for identification of genes, genomic regulatory regions and molecular networks involved in cardiac development and disease. We investigate the function of the candidate genes or elements by expression analysis in embryonic tissues and functional assays in cell models. Identification of genes associated with cardiac development and CHD is likely to have an impact on early diagnosis and prevention of CHD and may also provide a basis for development of new drug therapies e.g. for minor cardiac defects like small atrial- and ventricular defects. Furthermore, identifying and understanding molecular mechanisms in human cardiac development, especially the subset of genes and molecular networks which regulate cardiomyogenesis is likely to have an impact on the development of therapeutic means for regeneration of cardiomyocytes in myocardial infarction and congestive heart failure.


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Publications related to WJC

50.   Lage K, Greenway SC, Rosenfeld JA, Wakimoto H, Gorham JM, Segrè AV, Roberts AE, Smoot LB, Pu WT, Pereira AC, Mesquita SM, Tommerup N, Brunak S, Ballif BC, Shaffer LG, Donahoe PK, Daly MJ, Seidman JG, Seidman CE, Larsen LA. Genetic and environmental risk factors in congenital heart disease functionally converge in protein networks driving heart development. Proc Natl Acad Sci U S A. 2012;109:14035-40.
49.   Sørensen KM, El-Segaier M, Fernlund E, Errami A, Bouvagnet P, Nehme N, Steensberg J, Hjortdal V, Soller M, Behjati M, Werge T, Kirchoff M, Schouten J, Tommerup N, Andersen PS, Larsen LA. Screening of congenital heart disease patients using multiplex ligation-dependent probe amplification: Early diagnosis of syndromic patients. Am J Med Genet A. 2012;158A:720-5.
48.   Brøchner CB, Johansen JS, Larsen LA, Bak M, Mikkelsen HB, Byskov AG, Andersen CY, Møllgård K. Ykl-40 is Differentially Expressed in Human Embryonic Stem Cells and in Cell Progeny of the Three Germ Layers. J Histochem Cytochem. 2012;60:188-204.
47.   Larsen LA. [Chromosomal changes in congenital heart disease]. Ugeskr Laeger. 2011;173:194-6. Danish.
46.   Lage K, Møllgård K, Greenway S, Wakimoto H, Gorham JM, Workman CT, Bendsen E, Hansen NT, Rigina O, Roque FS, Wiese C, Christoffels VM, Roberts AE, Smoot LB, Pu WT, Donahoe PK, Tommerup N, Brunak S, Seidman CE, Seidman JG, Larsen LA. Dissecting spatio-temporal protein networks driving human heart development and related disorders. Mol Syst Biol. 2010 Jun 22;6:381.
45.   Thienpont B, Zhang L, Postma AV, Breckpot J, Tranchevent LC, Van Loo P, Møllgård K, Tommerup N, Bache I, Tümer Z, van Engelen K, Menten B, Mortier G, Waggoner D, Gewillig M, Moreau Y, Devriendt K, Larsen LA. Haploinsufficiency of TAB2 Causes Congenital Heart Defects in Humans. Am J Hum Genet. 2010;86:839-49.
44.   Sørensen KM, Agergaard P, Olesen C, Andersen PS, Larsen LA, Ostergaard JR, Schouten JP, Christiansen M. Detecting 22q11.2 deletions by use of multiplex ligation-dependent probe amplification on DNA from neonatal dried blood spot samples. J Mol Diagn. 2010;12:147-51.
43.   Christensen M, Larsen LA, Kauppinen S, Schratt G. Recombinant Adeno-Associated Virus-Mediated microRNA Delivery into the Postnatal Mouse Brain Reveals a Role for miR-134 in Dendritogenesis in Vivo. Front Neural Circuits. 2010;3:16.
42.   Clement CA, Larsen LA, Christensen ST. Using nucleofection of siRNA constructs for knockdown of primary cilia in P19.CL6 cancer stem cell differentiation into cardiomyocytes. Methods Cell Biol. 2009;94:181-97.
41.   Clement CA, Kristensen SG, Møllgård K, Pazour GJ, Yoder BK, Larsen LA, Christensen ST. The primary cilium coordinates early cardiogenesis and hedgehog signaling in cardiomyocyte differentiation. J Cell Sci. 2009;122:3070-82.
40.   Hilhorst-Hofstee Y, Tümer Z, Born P, Knijnenburg J, Hansson K, Yatawara V, Steensberg J, Ullmann R, Arkesteijn G, Tommerup N, Larsen LA. Molecular characterization of two patients with de novo interstitial deletions in 4q22-q24. Am J Med Genet A. 2009;149A:1830-3.
39.   Brudzewsky D, Pedersen AE, Claesson MH, Gad M, Kristensen NN, Lage K, Jensen T, Tommerup N, Larsen LA, Knudsen S, Tümer Z. Genome-wide gene expression profiling of SCID mice with T-cell-mediated Colitis. Scand J Immunol. 2009;69:437-46.
38.   Andersen PS, Havndrup O, Hougs L, Sørensen KM, Jensen M, Larsen LA, Hedley P, Bie Thomsen AR, Moolman-Smook J, Christiansen M, Bundgaard H. Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives. Hum Mutat. 2009;30:363-70.
37.   Jakobsen LP, Borup R, Vestergaard J, Larsen LA, Lage K, Maroun LL, Kjaer I, Niemann CU, Andersen M, Knudsen MA, Møllgård K, Tommerup N. Expression analyses of human cleft palate tissue suggest a role for osteopontin and immune related factors in palatal development. Exp Mol Med. 2009;41:77-85.
36.   Zhang L, Tümer Z, Møllgård K, Barbi G, Rossier E, Bendsen E, Møller RS, Ullmann R, He J, Papadopoulos N, Tommerup N, Larsen LA. Characterization of a t(5;8)(q31;q21) translocation in a patient with mental retardation and congenital heart disease: implications for involvement of RUNX1T1 in human brain and heart development. Eur J Hum Genet. 2009;17:1010-8.
35.   Sørensen KM, Andersen PS, Larsen LA, Schwartz M, Schouten JP, Nygren AO. Multiplex Ligation-Dependent Probe Amplification Technique for Copy Number Analysis on Small Amounts of DNA Material. Anal Chem. 2008;80:9363-8.
34.   Erdogan F, Larsen LA, Zhang L, Tumer Z, Tommerup N, Chen W, Jacobsen JR, Schubert M, Jurkatis J, Tzschach A, Ropers HH, Ullmann R. High frequency of submicroscopic genomic aberrations detected by tiling path array CGH in patients with isolated congenital heart disease. J Med Genet. 2008;45:704-9.
33.   Buysse K, Crepel A, Menten B, Pattyn F, Antonacci F, Veltman J, Larsen LA, Tumer Z, de Klein A, van de Laar I, Devriendt K, Mortier G, Speleman F. Mapping of 5q35 chromosomal rearrangements within a genomically unstable region. J Med Genet. 2008;45:672-8.
32.   Vestergaard J, Lind-Thomsen A, Pedersen MW, Ostergaard Jarmer H, Bak M, Hasholt L, Tommerup N, Tümer Z, Larsen LA. GLI1 Is Involved in Cell Cycle Regulation and Proliferation of NT2 Embryonal Carcinoma Stem Cells. DNA Cell Biol. 2008;27:251-6.
31.   Erdogan F, Belloso JM, Gabau E, Ajbro KD, Guitart M, Ropers HH, Tommerup N, Ullmann R, Tümer Z, Larsen LA. Fine mapping of a de novo interstitial 10q22-q23 duplication in a patient with congenital heart disease and microcephaly. Eur J Med Genet. 2008;51:81-6.
30.   Johansen JS, Høyer PE, Larsen LA, Price PA, Møllgård K. YKL-40 Protein Expression in the Early Developing Human Musculoskeletal System. J Histochem Cytochem. 2007;55:1213-28.
29.   Larsen LA, Jespersgaard C, Andersen PS. Single-strand conformation polymorphism analysis using capillary array electrophoresis for large-scale mutation detection. Nat Protoc. 2007;2:1458-66.
28.   Jakobsen LP, Ullmann R, Christensen SB, Jensen KE, Mølsted K, Henriksen KF, Hansen C, Knudsen MA, Larsen LA, Tommerup N, Tumer Z. Pierre Robin sequence may be caused by dysregulation of SOX9 and KCNJ2. J Med Genet. 2007;44:381-6.
27.   Dahl C, Gronskov K, Larsen LA, Guldberg P, Brondum-Nielsen K. A homogeneous assay for analysis of FMR1 promoter methylation in patients with fragile x syndrome. Clin Chem. 2007;53:790-3.
26.   Nielsen NH, Winkel BG, Kanters JK, Schmitt N, Hofman-Bang J, Jensen HS, Bentzen BH, Sigurd B, Larsen LA, Andersen PS, Haunso S, Kjeldsen K, Grunnet M, Christiansen M, Olesen SP. Mutations in the Kv1.5 channel gene KCNA5 in cardiac arrest patients. Biochem Biophys Res Commun. 2007;354:776-82.
25.   Zhang L, Tumer Z, Jacobsen JR, Andersen PS, Tommerup N, Larsen LA. Screening of 99 Danish patients with congenital heart disease for GATA4 mutations. Genet Test. 2006;10:277-80.
24.   Vuust J, Larsen LA, Grønskov K, Nørgaard-Pedersen B, Brøndum-Nielsen K. Screening for Fragilt X syndrom – Internationale erfaringer. Ugeskr Laeger. 2006:168:3704-9.
23.   Jespersgaard C, Larsen LA, Baba S, Kukita Y, Tahira T, Christiansen M, Vuust J, Hayashi K, Andersen PS. Optimization of capillary array electrophoresis single-strand conformation polymorphism analysis for routine molecular diagnostics. Electrophoresis. 2006;27:3816-22.
22.   Bak M, Conley L, Hedegaard J, Larsen LA, Sørensen P, Bendixen C, Tommerup N. Evaluation of two methods for generating cRNA for microarray experiments from nanogram amounts of total RNA. Anal Biochem. 2006;358:111-9.
21.   Vestergaard J, Pedersen MW, Pedersen N, Ensinger C, Tumer Z, Tommerup N, Poulsen HS, Larsen LA. Hedgehog signaling in small-cell lung cancer: Frequent in vivo but a rare event in vitro. Lung Cancer. 2006;52:281-90.
20.   Baekvad-Hansen M, Tumer Z, Delicado A, Erdogan F, Tommerup N, Larsen LA. Delineation of a 2.2 Mb microdeletion at 5q35 associated with microcephaly and congenital heart disease. Am J Med Genet A. 2006;140A:427-33.
19.   Tumer Z, Henriksen AM, Bache I, Brixen K, Kalschauer V, Illum N, Rasmussen K, Larsen LA, Tommerup N. Eponymous Jacobsen syndrome: Mapping the breakpoints of the original family suggests an association between the distal 1.1 Mb of chromosome 21 and osteoporosis in Down syndrome. Am J Med Genet A. 2005;135:339-41.
18.   Tian H, Emrich CA, Scherer J, Mathies RA, Andersen PS, Larsen LA, Christiansen M. High Throughput Single-Strand Conformation Polymorphism Analysis on a Microfabricated Capillary Array Electrophoresis Device. Electrophoresis. 2005;26:1834-42.
17.   Christiansen M, Tønder N, Larsen LA, Andersen PS, Simonsen H, Øyen N, Kanters JK, Jacobse, JR, Fosdal I, Wettrell G and Kjeldsen K. Mutations in the HERG ion channel: A novel link between long QT syndrome and sudden infant death syndrome. Am J Cardiol 2005;95:433-4.
16.   Boonen SE, Stahl D, Rosenberg T, Kreiborg S, Kalscheuer V, Larsen LA, Tommerup N, Brøndum-Nielsen K, Tumer Z. Delineation of an interstitial 9q22 deletion in basal cell nevus syndrome. Am J Med Genet A. 2005;132:324-8.
15.   Christiansen M, Kjeldsen K, Wettrell G, Larsen LA, Lundkvist L, Andersen PS, Tran CT, Kanters JK, Vuust J. Potassium Must Be Considered in Congenital long QT syndrome. Heart Drug. 2005;5:54-8.
14.   Frank-Hansen R, Larsen LA, Andersen PS, Jespersgård C, Christiansen M. Mutations in the genes KCND2 and KCND3 encoding the ion-channels Kv 4.2 and Kv 4.3, conducting the cardiac fast transient outward current (ITO,f), are not a frequent cause of Long QT syndrome. Clin Chim Acta. 2005;351:95-100.
13.   Henriksen AM, Tumer Z, Tommerup N, Tranebjærg L, Larsen LA. Identification of a novel EYA1 splice-site mutation in a Danish branchio-oto-renal syndrome family. Genet Test. 2004;8:404-6.
12.   Hougs L, Havndrup O, Bundgaard H, Køber L, Vuust J, Larsen LA, Christiansen M, Andersen PS. One-third of Danish hypertrophic cardiomyopathy patients with MYH7 mutations have mutations in rod region. Eur J Hum Genet. 2005;13:161-5.
11.   Kanters JK, Fanoe S, Larsen LA, Bloch-Thomsen PE, Toft E, Christansen M. T-wave pattern morphology analysis distinguishes between KvLQT1 and HERG mutations in Long QT syndrome. Heart Rhythm. 2004;3:285-292.
10.   Andersen PS, Havndrup O, Bundgaard H, Larsen LA, Børglum AD, Vuust J, Pedersen AK, Kjeldsen K, Christiansen M. Genetic and phenotypic characterization of mutations in myosin-binding protein C (MYBPC3) in 81 families with familial hypertrophic cardiomyopathy: total or partial haploinsufficiency. Eur J Hum Genet. 2004;12:673-7.
9.   Grønskov K, Larsen LA, Rendtorff ND, Parving A, Nørgaard-Pedersen B, Brøndum-Nielsen K. GJB2 and GJB6 mutations in 165 Danish patients showing non-syndromic hearing impairment. Genet Test. 2004;8:181-4.
8.   Hofman-Bang J, Jespersen T, Grunnet M, Larsen LA, Andersen PS, Kanters JK, Kjeldsen K and Christiansen M. Does KCNE5 play a role in long QT syndrome?. Clin Chim Acta. 2004;345:49-53.
7.   Bak M, Hansen C, Tommerup N, Larsen LA. The Hedgehog signaling pathway-implications for drug targets in cancer and neurodegenerative disorders. Pharmacogenomics. 2003;4:411-29 (Review).
6.   Andersen PS, Jespersgaard C, Vuust J, Christiansen M, Larsen LA. Capillary electrophoresis-based single strand DNA conformation analysis in high-throughput mutation screening. Hum Mutat. 2003;21:455-65.
5.   Larsen LA, Christiansen M, Vuust J, Andersen PS. Single-strand conformation polymorphism analysis using capillary electrophoresis. Curr Protoc Hum Genet. 2003;Chapter 7:Unit 7.12.
4.   Andersen PS, Jespersgaard C, Vuust J, Christiansen M, Larsen LA. High-throughput single strand conformation polymorphism mutation detection by automated capillary array electrophoresis: validation of the method. Hum Mutat. 2003;21:116-22.
3.   Havndrup O, Bundgaard H, Andersen PS, Larsen LA, Vuust J, Kjeldsen K, Christiansen M. Outcome of clinical versus genetic family screening in hypertrophic cardiomyopathy with focus on cardiac beta-myosin gene mutations. Cardiovasc Res. 2003;57:347-57.
2.   Andersen PS, Havndrup O, Bundgaard H, Moolman-Smook JC, Larsen LA, Mogensen J, Brink PA, Børglum AD, Corfield VA, Kjeldsen K, Vuust J, Christiansen M. Myosin light chain mutations in familial hypertrophic cardiomyopathy: their phenotypic presentation and frequency in Danish and South African populations. J Med Genet. 2001;38:e43 (doi: 10.1136/jmg.38.12.e43).
1.   Larsen LA, Christiansen M, Vuust J, Andersen PS. Recent developments in high-throughput mutation screening. Pharmacogenomics. 2001;2:387-99.

Book chapters related to WJC

5.   Ajbro KD, Larsen LA. The genetics of human congenital heart disease. In: Mikhailov A, Torrado M (eds.). Shaping the Heart in Development and Disease. Trivandrum 2010, Research Signpost, pp 193-216 2010.
4.   Clement CA, Larsen LA, Christensen ST. Using nucleofection of siRNA constructs for knockdown of primary cilia in P19.CL6 cancer stem cell differentiation into cardiomyocytes. In: Sloboda RD (eds.). Methods in Cell Biology. Amsterdam 2009, Elsevier. pp. 181-197.
3.   Vestergaard J, Bak M, Larsen LA. The Hedgehog Signaling Pathway in Cancer. In: Macieira-Coelho, Alvaro (eds.). Developmental Biology of Neoplastic Growth, Progress in Molecular and Subcellular Biology, Vol. 40. Heidelberg 2005, Springer.
2.   Andersen PS, Larsen LA. High Throughput Mutation Screening. In: Rapley R, Harbron S (eds.). Molecular Analysis and Genome Discovery. New York 2004, John Wiley & Sons, inc.
1.   Larsen LA, Christiansen M, Vuust J, Andersen PS. Single strand conformation polymorphism analysis using capillary electrophoresis. In: Dracopoli NC, Haines JL, Korf BR, Morton CC, Seidman CE, Seidman JG, Smith DR (eds.). Current Protocols in Human Genetics. New York 2002, John Wiley & Sons, inc. pp 7.12.1-7.12.8.

Presentations related to WJC

58th Annual Meeting of The American Society of Human Genetics
Philadelphia, Pennsylvania, November 11, 2008
17.   Larsen LA, Lage K, Møllgård K, Workman CT, Bendsen E, Tommerup N, Brunak S. Systematic Identification of Functional Networks in Human Heart Development.
Seminar, Gaungxi Cancer Institute, Nanning, China
Gaungxi Cancer Institute, Nanning, China, October 14, 2008
Oral presentations
16.   Larsen LA. Hedgehog Signaling in Development and Cancer.
DSMG meeting: systems biology in relation to genetics
Odense University Hospital, September 05, 2008
Oral presentations
15.   Larsen LA. Systematic identification of functional networks in human heart development.
Hjerteforeningens Børneklub familiekursus
Scandic Bygholm Parkhotel, Horsens, August 17, 2008
Oral presentations
14.   Larsen LA. På sporet af? Genetiske årsager til medfødt hjertemisdannelse.
The European Human Genetics Conference 2008
Barcelona, Spain, May 31, 2008
13.   Sørensen KM, Andersen PS, Larsen LA, Schwartz M, Schouten J, Nygren A. A novel MLPA technique for copy number analysis on small amounts of DNA.
American Society of Cell Biology
Washington, December 01, 2007
12.   Clement CA, Kristensen SG, Yoder B, Tümer Z, Christensen ST, Larsen LA. The primary cilium coordinates hedgehog signaling in the mouse P19.CL6 embryonal carcinoma stem cells.
Dansk Selskab for medfødte Hjertesygdomme
Odense Universitetshospital, November 15, 2007
Oral presentations
11.   Larsen LA. Genetiske årsager til medfødte hjertesygdomme.
American Society of Human Genetics
San Diego, October 23, 2007
10.PDF  Larsen LA, Zhang L, Barbi G, Møllgård K, Bendsen E, Møller R, Ullmann R, Tümer Z, Tommerup N. The leukemia associated gene RUNX1T1 (MTG8/ETO) is involved in heart and brain development.
European Human Genetics Conference 2007
Nice, France, June 16, 2007
9.   Erdogan F, Larsen LA, Zhang L, Tümer Z, Tommerup N, Chen W, Jacobsen JR, Schubert M, Jurkatis J, Tzschach A, Ropers H H, Ullmann R. High Frequency of Submicroscopic DNA copy number changes in patients with congenital heart disease.
30th FEBS Congress - 9th IUBMB Conference
Budapest, Hungary, July 02, 2005
8.PDF  Vestergaard J, Pedersen MW, Hasholt L, Tommerup N, Tumer Z and Larsen LA. siRNA mediated knock-down of the Hedgehog pathway member GLI1 inhibits the proliferation of NT2 neuronal precursor cells.
European Human Genetics Conference 2005 (ESHG 2005)
Prague, May 07, 2005
7.PDF  Larsen LA, Bækvad-Hansen M, Delicado A, Kalscheuer V, Tommerup N, Tumer Z. Delineation of a 5q35 microdeletion in congenital heart disease: haploinsufficiency of NKX2-5 can cause Ebstein anomaly.
54th Meeting of the American Society of Human Genetics
Toronto, Canada, October 25, 2004
6.PDF  Brudzewsky D, Larsen LA, Claesson M, Gad M, Kristensen NN, Knudsen S, Tumer Z. Genome-wide expression analysis in a mouse model of chronic inflammatory bowel disease.
The 4th European Mucosal Immunology Group Meeting
Lyon, France, October 07, 2004
5.PDF  Brudzewsky D, Larsen LA, Claesson M, Gad M, Kristensen NN, Knudsen S, Tumer Z. Genome-wide expression analysis in a mouse model of chronic inflammatory bowel disease.
European Human Genetics Conference 2003
Birmingham, England, May 02, 2003
4.PDF  Larsen LA, Henriksen KF, Christensen EL, Hasholt L, Tommerup N. Down regulation of the Sonic Hedgehog signalling pathway during neuronal differentiation of human teratocarcinoma (NT2) cells.
52nd Annual Meeting of The American Society of Human Genetics
Baltimore, Maryland, USA, October 14, 2002
3.   Frank-Hansen R, Larsen LA, Andersen PS, Jespersgaard C, Christiansen M. Mutations in the genes KCND2 and KCND3 encoding the ion-channels conducting the cardiac transient outward current (ITO) is not a frequent cause of long QT syndrome. Am J Human Genet 2002;71(supp):521 (Poster 2059).
2.   Andersen PS, Jespersgaard C, Brown C, Vuust J, Christiansen M, Larsen LA. High throughput automated mutation discovery. Am J Human Genet 2002;71(supp):406 (Poster 1377).
1.   Christiansen M, Tønder N, Larsen LA, Andersen PS, Simonsen H, Oyen N, Kanters JK, Jacobsen JR, Fosdall I, Wettrell G, Kjeldsen K. Mutations in the HERG ion channel: A novel link between long QT syndrome and sudden infant death syndrome. Am J Human Genet 2002;71(supp):323 (Poster 880).

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