Paulussen A, Raes A, Matthijs G, Snyders DJ, Cohen N, Aerssens J. A novel mutation (T65P) in the PAS domain of the human potassium channel HERG results in the long QT syndrome by trafficking deficiency. J Biol Chem 2002 Dec 13;277(50):48610-6.

Loos RJ, Phillips DI, Fagard R, Beunen G, Derom C, Mathieu C, Verhaeghe J, Vlietinck R. The influence of maternal BMI and age in twin pregnancies on insulin resistance in the offspring. Diabetes Care. 2002 Dec;25(12):2191-6.

Jongbloed R, Marcelis C, Velter C, Doevendans P, Geraedts J, Smeets H. DHPLC analysis of potassium ion channel genes in congenital long QT syndrome. Hum Mutat. 2002 Nov;20(5):382-91. 

Derom C, Vlietinck R, Thiery E, Leroy F, Fryns JP, Derom R. The East Flanders Prospective Twin Survey (EFPTS). Twin Res. 2002 Oct;5(5):337-41. Review. 

Wichers MC, Purcell S, Danckaerts M, Derom C, Derom R, Vlietinck R, Van Os J. Prenatal life and post-natal psychopathology: evidence for negative gene-birth weight interaction. Psychol Med. 2002 Oct;32(7):1165-74.

Covaci A, Koppen G, Van Cleuvenbergen R, Schepens P, Winneke G, van Larebeke N, Nelen V, Vlietinck R, Schoeters G. Persistent organochlorine pollutants in human serum of 50-65 years old women in the Flanders Environmental and Health Study (FLEHS). Part 2: Correlations among PCBs, PCDD/PCDFs and the use of predictive markers. Chemosphere. 2002 Sep;48(8):827-32.

Koppen G, Covaci A, Van Cleuvenbergen R, Schepens P, Winneke G, Nelen V, van Larebeke N, Vlietinck R, Schoeters G. Persistent organochlorine pollutants in human serum of 50-65 years old women in the Flanders Environmental and Health Study (FLEHS). Part 1: Concentrations and regional differences. Chemosphere. 2002 Sep;48(8):811-25.

Vliegen I, Stassen F, Grauls G, Blok R, Bruggeman C. MCMV infection increases early T-lymphocyte influx in atherosclerotic lesions in apoE knockout mice. J Clin Virol. 2002 Aug;25 Suppl 2:S159-71

Vermeire S, Louis E, Rutgeerts P, De Vos M, Van Gossum A, Belaiche J, Pescatore P, Fiasse R, Pelckmans P, Vlietinck R, Merlin F, Zouali H, Thomas G, Colombel JF, Hugot JP. NOD2/CARD15 does not influence response to infliximab in Crohn's disease. Gastroenterology. 2002 Jul;123(1):106-11. 

Van Den Heuvel RL, Koppen G, Staessen JA, Hond ED, Verheyen G, Nawrot TS, Roels HA, Vlietinck R, Schoeters GE. Immunologic biomarkers in relation to exposure markers of PCBs and dioxins in Flemish adolescents (Belgium). Environ Health Perspect. 2002 Jun;110(6):595-600.

Eurlings PM, Van Der Kallen CJ, Geurts JM, Kouwenberg P, Boeckx WD, De Bruin TW. Identification of differentially expressed genes in subcutaneous adipose tissue from subjects with familial combined hyperlipidemia. J Lipid Res 2002 Jun;43(6):930-5

Vinck WJ, Fagard RH, Vlietinck R, Lijnen P. Heritability of plasma renin activity and plasma concentration of angiotensinogen and angiotensin-converting enzyme. J Hum Hypertens. 2002 Jun;16(6):417-22.

Loos RJ, Beunen G, Fagard R, Derom C, Vlietinck R. Birth weight and body composition in young women: a prospective twin study. Am J Clin Nutr. 2002 Apr;75(4):676-82. 

Huygens W, Claessens AL, Thomis M, Loos R, Van Langendonck L, Peeters M, Philippaerts R, Meynaerts E, Vlietinck R, Beunen G. Body composition estimations by BIA versus anthropometric equations in body builders and other power athletes. J Sports Med Phys Fitness. 2002 Mar;42(1):45-55.

Conrath CE, Wilde AA, Jongbloed RJ, Alders M, van Langen IM, van Tintelen JP, Doevendans PA, Opthof T. Gender differences in the long QT syndrome: effects of beta-adrenoceptor blockade. Cardiovasc Res. 2002 Feb 15;53(3):770-6.

van Ravenswaaij-Arts CM, van den Ouweland AM, Hoogeboom AJ, Herbergs J, Pals G. [From gene to disease; craniosynostosis syndromes due to FGFR2-mutation] Ned Tijdschr Geneeskd. 2002 Jan 12;146(2):63-6. Review.

Jacobs N, Rijsdijk F, Derom C, Danckaerts M, Thiery E, Derom R, Vlietinck R, van Os J. Child psychopathology and lower cognitive ability: a general population twin study of the causes of association. Mol Psychiatry. 2002;7(4):368-74.

Esters N, Pierik M, Claessens G, Joossens G, Vermeire S, Vlietinck R, Rutgeerts P. NOD2/CARD15 mutations in a Flemish inflammatory bowel disease (IBB) population. Gastroenterology 2002, 122(4):1419.

Esters N, Pierik M, Claessens G, Joossens S, Vermeire S, Vlietinck R, Rutgeerts P. Mutations in NOD2/CARD15 in Crohn’s disease patients and their unaffected siblings. Gastroenterology 2002, 122(4):1406-1412

Jacobs N, Derom C, Hanssen M, Vlietinck R, van Os J. Causes of association between three dimensions of psychosis in a general population twin sample. Acta Psychiat Scand 2002, 105:117.

Matthijs K, Van de Putte B, Vlietinck R. The inheritance of longevity in a Flemish village (18th-20th century). Eur J Pop 2002, 18(1):59-81. Loos RJF, Derom C, Eeckels R, Derom R, Vlietinck R. Gestation and birthweight in dizygotic twins – Reply. Lancet 2002,359(9301):172.

Duchateau, L., Janssen, P., Lindsey, P.J., Legrand, C., Nguti, R., and Sylvester, R. The shared frailty model and the power for heterogeneity tests in multicenter trials. Computational Statistics and Data Analysis 40, 2002,603-620


The characterization of genes with different expression levels in mouse blastocyst inner cell mass cells and trophectoderm cells.
 J.C.F.M. Dreesen1, M. Bras2, J.G. Derhaag2, J.C.M. Dumoulin2, E. Coonen2, H.J.M. Smeets1, J.L.H. Evers2, J.P.M. Geraedts1, J. Herbergs1. 1) Clinical Genetics, Academic Hospital Maastricht, Maastricht, The Netherlands; 2) Obstetrics and Gynaecology, Academic Hospital Maastricht, The Netherlands. The blastocyst represents the embryonic stage in which differentiation of embryonic cells into trophectoderm (TE) and the inner cell mass (ICM) has occurred. Using immunosurgery and mechanical separation, ICM- or TE-cells can be divided and isolated from the blastocyst. In this study blastocysts were obtained from superovulated (C57Bl/6XCBA)F1 mice in vivo fertilized by random-bred Swiss males. ICM- and TE-cells were isolated from single blastocysts. mRNA was purified and cDNA was transcribed and amplified with the SMART cDNA synthesis kit. Differential display PCR was performed on replicate ICM, TE samples and total blastocyst cDNA samples, followed by separation of the PCR fragments on a denaturing polyacrylamide gel. ICM- and TE-specific bands as well as shared bands present in ICM, TE and total blastocysts (controls) were isolated from the gel, amplified and sequenced. Sequences were annotated by BLAST searches in the commercial CELERA and public NCBI and MGD nucleotide sequence databases. 25 of the 52 isolated fragments could be directly sequenced and annotated according to NCBI nomenclature. Comparison of TE-cells with ICM-cells showed differential expression of five of 7 identified genes and 2 of 3 anonymous cDNA sequences. Furthermore, three control sequences equally expressed in the blastocyst, ICM- and TE-cells, showed consistent results with respect to sequencing and annotation. In conclusion we have isolated, sequenced and annotated sequences from transcripts differentially expressed in ICM- and TE-cells. Equal expression of control sequences showed the feasibility of this method. Differentially expressed genes are currently being confirmed and will be quantified by quantitative PCR analysis and evaluated for their role in blastocyst formation and implantation.


Mutations in the TGIF gene and SIX3 gene in patients with holoprosencephaly.
J. Herbergs1, H.W. Moerland1, J.J. Van der Smagt3, G.M.S. Mancini2, M. Van Haelst2, H.J.M. Smeets1. 1) Department of Clinical Genetics, Academic Hospital Maastricht, Maastricht, The Netherlands; 2) Department of Clinical Genetics, Erasmus University, Rotterdam, The Netherlands; 3) Leiden University Medical Hospital, Leiden, The Netherlands. Holoprosencephaly (HPE) is a common, severe malformation of the brain that involves abnormal formation and septation of the developing central nervous system. In mild HPE microcephaly, a single central incisor, hypotelorism or other craniofacial findings can be present with or without associated malformations. Mutations in several genes are known to cause HPE. In our lab four genes known to be involved in the pathogenenesis of HPE are initially analysed for pathogenic mutations, namely SHH, ZIC2, SIX3 and TGIF. In a small series of patients a new truncating mutation was detected in the SIX3 gene and a missense mutation in the TGIF gene. The patient with a SIX3 mutation has semilobar HPE with cleft palate, while the patient with a TGIF mutation presented with more severe HPE. The mutation in the TGIF gene could affect a region of the protein constituting a repression domain, which is dependent on HDAC and contains a SMAD-interacting region. The mutation, however, was also detected in one of the parents, presenting hypotelorism and microcephaly


ELUCIDATION OF PATHOGENIC GENETIC PATHWAYS IN THE HYPERTROPHIC AND FAILING HEART BY MICROARRAY TECHNOLOGY. H. Smeets1,2, B. Van den Bosch1,2, S. Van der Vlies1,2, J. Geurts1,2, I. De Coo3, H. Scholte3, D. Lips2, P. Doevendans2. 1) Dept Genetics & Cell Biol, Univ Maastricht, Maastricht, Netherlands; 2) CARIM, Univ Maastricht, Maastricht, The Netherlands; 3) Dept Pediatric Neurology and Biochemistry, Erasmus University, Rotterdam. Gene expression differences between normal, hypertrophic and failing heart may provide therapeutic targets for interventions in patients. To circumvent the complexity and scarcity of human biopsies, we used inbred mice, in which Transverse Aortic Banding (TAC) was applied to induce cardiac hypertrophy, followed by heart failure. Left ventricle RNA of these mice and controls (48 hours, 1, 2, 3,6 and 8 weeks after operation) was labeled with Cy3/Cy5 (indirect amino-allyl-labeling) and hybridized to microarrays containing ~4,000 cDNA clones derived from adult and fetal mouse heart. Experiments were performed in quadruplicate, using at least 3 mice per time point. Scatter plots showed that expression levels of the majority of genes was unaltered. Known hypertrophy markers (f.e. betaMHC, ANP, SPARC, CARP) were elevated as expected. Initial results showed >2-fold altered gene expression of a number of unknown and known genes, including connective tissue growth factors, imprinted mesoderm specific embryonic genes and calcineurin-interacting proteins in the hypertrophic myocard after 7 days. Specific mitochondrial genes displayed a decrease after 42 days, when heart failure could be observed. Gene expression changes were confirmed by quantitative PCR and related to functional changes, in the latter case for example by measuring respiratory chain enzyme activities. Our next step will be to test the differentially expressed genes in human biopsy specimens of non-diseased, hypertrophic and failing myocard. The newly identified genes will be evaluated for a role in familiar hypertrophic or dilated cardiomyopathy by their map position and segregation in families.