Publications 2008


Konings A, Van Camp G, Goethals A, Van Eyken E, Vandevelde A, Ben Azza J, Peeters N, Wuyts W, Smeets H, Van Laer L. Mutation analysis of mitochondrial DNA 12SrRNA and tRNASer(UCN) genes in non-syndromic hearing loss patients. Mitochondrion. 2008 Dec;8(5-6):377-82. SCI 3.209.

Smeets PJ, de Vogel-van den Bosch HM, Willemsen PH, Stassen AP, Ayoubi T, van der Vusse GJ, van Bilsen M. Transcriptomic analysis of PPAR{alpha}-dependent alterations during cardiac hypertrophy. Physiol Genomics. 2008 Dec 12;36(1):15-23.

Verdijk RM, de Krijger R, Schoonderwoerd K, Tiranti V, Smeets H, Govaerts LC, de Coo R. Phenotypic consequences of a novel SCO2 gene mutation. Am J Med Genet A. 2008 Nov 1;146A(21):2822-7. SCI 2.440.

Bredenoord AL, Dondorp W, Pennings G, De Die-Smulders CE, De Wert G. PGD to reduce reproductive risk: the case of mitochondrial DNA disorders. Hum Reprod. 2008 Nov;23(11):2392-401. SCI 3.543

van Steensel MA, Vreeburg M, Engelen J, Ghesquiere S, Stegmann AP, Herbergs J, van Lent J, Smeets B, Vles JH. Contiguous gene syndrome due to a maternally inherited 8.41 Mb distal deletion of chromosome band Xp22.3 in a boy with short stature, ichthyosis, epilepsy, mental retardation, cerebral cortical heterotopias and Dandy-Walker malformation. Am J Med Genet A. 2008 Nov 15;146A(22):2944-9. SCI 2.440

Souren NY, Paulussen AD, Steyls A, Loos RJ, Stassen AP, Gielen M, Smeets HJ, Beunen G, Fagard R, Derom C, Vlietinck R, Geraedts JP, Zeegers MP. Common SNPs in LEP and LEPR associated with birth weight and type 2 diabetes-related metabolic risk factors in twins. Int J Obes (Lond). 2008 Nov;32(11):1745-1746. SCI 3.560

 

Dreesen J, Drüsedau M, Smeets H, de Die-Smulders C, Coonen E, Dumoulin J, Gielen M, Evers J, Herbergs J, Geraedts J. Validation of preimplantation genetic diagnosis by PCR analysis: genotype comparison of the blastomere and corresponding embryo, implications for clinical practice. Mol Hum Reprod. 2008 Oct;14(10):573-9. SCI 2.871.
 

Frints SG, Lenzner S, Bauters M, Jensen LR, Van Esch H, des Portes V, Moog U, Macville MV, van Roozendaal K, Schrander-Stumpel CT, Tzschach A, Marynen P, Fryns JP, Hamel B, van Bokhoven H, Chelly J, Beldjord C, Turner G, Gecz J, Moraine C, Raynaud M, Ropers HH, Froyen G, Kuss AW.  MCT8 mutation analysis and identification of the first female with Allan-Herndon-Dudley syndrome due to loss of MCT8 expression. Eur J Hum Genet. 2008 Sep;16(9):1029-37 SCI 4.003
 

Troost FJ, Van Baarlen P, Lindsey P, Kodde A, De Vos WM, Kleerebezem M, Brummer RJ. Identification of the transcriptional response of human intestinal mucosa to Lactobacillus plantarum WCFS1 in vivo. BMC Genomics. 2008 Aug 5;9(1):374. SCI 3.613
 

Smits KM, Smits LJ, Peeters FP, Schouten JS, Janssen RG, Smeets HJ, van Os J, Prins MH. The influence of 5-HTTLPR and STin2 polymorphisms in the serotonin transporter gene on treatment effect of selective serotonin reuptake inhibitors in depressive patients. Psychiatr Genet. 2008 Aug;18(4):184-90. SCI 2.257

Souren NY, Paulussen AD, Steyls A, Loos RJ, Stassen AP, Gielen M, Smeets HJ, Beunen G, Fagard R, Derom C, Vlietinck R, Geraedts JP, Zeegers MP. Common SNPs in LEP and LEPR associated with birth weight and type 2 diabetes-related metabolic risk factors in twins. Int J Obes (Lond). 2008 Aug;32(8):1233-9. SCI 3.560
 

van Eijsden R, Eijssen L, Lindsey P, van den Burg C, de Wit E, Rubio-Gozalbo E, de Die C, Ayoubi T, Sluiter W, de Coo I, Smeets H. Termination of damaged protein repair defines the occurrence of symptoms in carriers of the m.3243A>G tRNALeu mutation.  J Med Genet. 2008 Aug 45(8):525-34. SCI 5.535
 

Bebarova M, O'Hara T, Geelen JL, Jongbloed RJ, Timmermans C, Arens YH, Rodriguez LM, Rudy Y, Volders PG. Subepicardial phase-0 block and discontinuous transmural conduction underlie right-precordial ST-segment elevation by a SCN5A loss-of-function mutation. Am J Physiol Heart Circ Physiol. 2008 Jul;295(1):H48-58. SCI 3.973
 

Poelmans G, Engelen JJ, Van Lent-Albrechts J, Smeets HJ, Schoenmakers E, Franke B, Buitelaar JK, Wuisman-Frerker M, Erens W, Steyaert J, Schrander-Stumpel C.  Identification of novel dyslexia candidate genes through the analysis of a chromosomal deletion.  Am J Med Genet B Neuropsychiatr Genet. 2008 Jun 2;. [Epub ahead of print] SCI 5.535

Hanse MC, Gerrits MC, van Rooij WJ, Houben MP, Nijssen PC, Sluzewski M. Recovery of posterior communicating artery aneurysm-induced oculomotor palsy after coiling. Am J Neuroradiol. 2008 May;29(5):988-90. SCI 2.338.

Beetz C, Schüle R, Deconinck T, Tran-Viet KN, Zhu H, Kremer BP, Frints SG, van Zelst-Stams WA, Byrne P, Otto S, Nygren AO, Baets J, Smets K, Ceulemans B, Dan B, Nagan N, Kassubek J, Klimpe S, Klopstock T, Stolze H, Smeets HJ, Schrander-Stumpel CT, Hutchinson M, van de Warrenburg BP, Braastad C, Deufel T, Pericak-Vance M, Schöls L, de Jonghe P, Züchner S. REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31. Brain. 2008 Apr;131(Pt 4):1078-86. SCI 8.568
 

Gielen M, Lindsey PJ, Derom C, Loos RJ, Souren NY, Paulussen AD, Zeegers MP, Derom R, Vlietinck R, Nijhuis JG. Twin-Specific Intrauterine 'Growth' Charts Based on Cross-Sectional Birthweight Data. Twin Res Hum Genet. 2008 Apr;11(2):224-235. SCI 1.525
 

Nemes A, De Coo IF, Spruijt L, Smeets HJ, Chinnery PF, Soliman OI, Geleijnse ML, Ten Cate FJ. Is there alteration in aortic stiffness in Leber hereditary optic neuropathy? Eur J Ophthalmol. 2008 Mar-Apr;18(2):309-12. SCI 4.621
 

de Jong J, Stoop H, Gillis AJ, Hersmus R, van Gurp RJ, van de Geijn GJ, van Drunen E, Beverloo HB, Schneider DT, Sherlock JK, Baeten J, Kitazawa S, van Zoelen EJ, van Roozendaal K, Oosterhuis JW, Looijenga LH. Further characterization of the first seminoma cell line TCam-2. Genes Chromosomes Cancer. 2008 Mar;47(3):185-96. SCI 4.532

van Montfoort AP, Geraedts JP, Dumoulin JC, Stassen AP, Evers JL, Ayoubi TA. Differential gene expression in cumulus cells as a prognostic indicator of embryo viability: a microarray analysis. Mol Hum Reprod. 2008 Mar;14(3):157-68. SCI 2.871

 

Eijssen LM, Lindsey PJ, Peeters R, Westra RL, van Eijsden RG, Bolotin-Fukuhara M, Smeets HJ, Vlietinck RF. A novel stepwise analysis procedure of genome-wide expression profiles identifies transcript signatures of thiamine genes as classifiers of mitochondrial mutants. Yeast. 2008 Feb;25(2):129-40. SCI 1.955

Bredenoord AL, Pennings G, Smeets HJ, de Wert G. Dealing with uncertainties: ethics of prenatal diagnosis and preimplantation genetic diagnosis to prevent mitochondrial disorders. Hum Reprod Update. 2008 Jan-Feb;14(1):83-94. SCI 7.257.

Gielen M, Lindsey PJ, Derom C, Smeets HJ, Souren NY, Paulussen AD, Derom R, Nijhuis JG. Modeling Genetic and Environmental Factors to Increase Heritability and Ease the Identification of Candidate Genes for Birth Weight: A Twin Study. Behav Genet. 2008 Jan;38(1):44-54. SCI 2.634

Eijssen LM, van den Bosch BJ, Vignier N, Lindsey PJ, van den Burg CM, Carrier L, Doevendans PA, van der Vusse GJ, Smeets HJ Altered myocardial gene expression reveals possible maladaptive processes in heterozygous and homozygous cardiac myosin-binding protein C knockout mice. Genomics 2008 Jan;91(1):52-60  SCI 3.558

 

 

POSTERS

 

ESHG

 

Evaluation and validation of Preimplantation Genetic Diagnosis PGD) by PCR analysis: comparison of the blastomere and corresponding embryo genotype

J. Herbergs1,2, M. Drusedau1, H. Smeets1,2, C. De Die-Smulders1, J. Dumoulin1, J. Evers1, J. Dreesen1,2, J. Geraedts1,2; 1Academic Hospital Maastricht, Maastricht, The Netherlands, 2Maastricht University, Maastricht, The Netherlands. PGD can be an alternative for prenatal diagnosis for couples at high risk of a monogenic disorder. The aim of the present study is to validate the PGD-PCR procedure, and determine the diagnostic value. According to embryo morphology quality scores, embryos on day 4 post fertilization were divided into class 1-4, with class 4 being the lowest embryo morphology score. The genotype from the biopsied blastomere and the corresponding embryo were compared. To establish the validity of PGD-PCR procedure, sensitivity(Se), specificity(Sp), and Likelihood Ratio(LR) were calculated for the total, class 4 excluded and class 4 embryo group. For the diagnostic value, Positive- (PPV) and Negative Predictive Value (NPV) were calculated. In our centre 80 women underwent PGD-PCR, resulting in 793 embryo genotypes, 241 unaffected embryos were used for ET. PGD-PCR blastomere outcome, scored as affected or aberrant in 234/241 positive embryos (Se; 97,1%), and scored unaffected in 181/206 negative embryos (Sp: 87,9%). Out of the 7 false negative embryos, 6 were graded as class 4. The Se in the class 4 embryo group was 90,2% and Sp 93,2%. Exclusion of class 4 embryos resulted in Se of 99,4%, Sp of 86,4% and LR positive test of 7.3 and LR negative test of 0.006. The PPV of an abnormal PGD-PCR is 89.1%, the NPV of a normal PGDPCR is 99.3% in this group. PGD-PCR procedure is validated as a diagnostically reliable method for selecting unaffected embryos for ET. Accuracy of PGD-PCR analysis improves by rejecting class 4 embryos for ET.  

 

Holoprosencephaly mutations in the Dutch population

A. D. Paulussen, D. Tserpelis, S. Spierts, H. J. Smeets, J. Herbergs; Academic Hospital Maastricht, Maastricht, The Netherlands. Holoprosencephaly (HPE) is a common severe malformation of the brain that involves abnormal formation and septation of the developing central nervous system. The prevalence is 1:250 during early embryogenesis, but the live born prevalence is only 1:16000. The etiology of HPE is extremely heterogeneous and can include both a teratogenic and/or genetic basis. We studied four genes known to be involved in HPE, namely SHH, ZIC2, SIX3 and TGIF by sequence and MLPA analysis. A series of in total 72 sporadic and familial HPE cases with a variable clinical spectrum has been analysed. We detected 17 pathogenic mutations (24%) in total, of which 2 in SHH, 6 in ZIC2 and 9 in SIX3. Only one mutation (Alanine-tract expansion in ZIC2) was reported previously and detected twice in this population, all others were novel. Two mutations were complete gene deletions (one SIX3, one ZIC2 deletion) of which the deletion sizes were further characterized using the 250K nsp I Affymetrix SNP array. The familial mutations displayed great phenotypic heterogeneity of the disease, which makes it difficult to establish genotype-phenotype correlations. This phenotypic variability may be due both to environmental factors and to potential modifier genes. HPE development is probably a multihit process , which implicates more genes; illustrating the importance of further identification of new genes.   

 

First Dutch founder mutation in Hereditary Spastic Paraplegia

W. A. G. van Zelst-Stams 1,2, S. G. M. Frints1,2, M. Gerards1,2, E. L. C. Jongen1,2, R. G. Janssen1, C. E. M. de Die-Smulders1,2, C. T. R. M. Schrander-Stumpel1,2, H. J. Smeets1,2; 1department of clinical genetics, university hospital Maastricht, Maastricht, The Netherlands, 2The Netherlands Research Institute GROW, Maastricht University, Maastricht, The Netherlands. Hereditary spastic paraplegia (HSP) is characterized by clinical and molecular heterogeneity. In autosomal dominant (AD) spastic paraplegia (SPG), SPASTIN (SPG4) and ATLASTIN (SPG3A) gene defects account for approximately 40% and 10%, respectively. We performed parametric linkage analysis, using the Affymetrix 10K SNP array, to identify the SPG locus in a ten-generation Dutch pedigree. A maximum LOD score of 5.03 was obtained at the SPG31 locus (2p11-p12). Mutation analysis of the receptor expression-enhancing protein 1 gene (REEP1) was performed in 10 additional AD SPG families from the South-East part of the Netherlands. A truncating four basepair deletion in exon six (c.537_540delCGGC p.Ser179ArgfsX43) was identified which co-segregated with the disorder in the large linked family and in two other small unrelated families, suggesting a founder effect in our region. A founder effect was confirmed by haplotype analysis using polymorphic markers surrounding REEP1. The clinical features within these families ranged from normal to severe spasticity of legs and the age of onset varied from birth till >75 years of age. There was an inverse correlation between age at onset and severity and progression of symptoms. Further functional studies are needed to identify a major modifier in REEP1 affected families. In conclusion, we identified a founder REEP1 mutation in 27% (3/11) of the AD pure SPG families investigated in the South-East part of the Netherlands. Thus REEP1 gene defects in HSP seem at least as common as ATLASTIN (SPG3A).

 

 

ASHG

 

 Termination of damaged protein repair defines the occurrence of symptoms in carriers of the m.3243A>G tRNA-Leu mutation.

H. Smeets1, R. van Eijsden1, L. Eijssen1, P. Lindsey1, C. van den Burg1, L. de Wit2, M. Rubio-Gozalbo3, C. de Die1, T. Ayoubi1,W. Sluiter2, I. deCoo2. 1) Dept Gen & Cell Biol, Univ Maastricht, Maastricht, Netherlands; 2) Department of Biochemistry, Mitochondrial Research Unit, Erasmus MC, Rotterdam - The Netherlands; 3) Department of Paediatrics and Laboratory Genetic  metabolic Diseases, Maastricht University Hospital, Maastricht - The Netherlands. The m.3243A>G mutation in the mtDNA tRNALeu gene displays a heterogeneous phenotypic expression. It is the most frequent cause (80%) of the MELAS syndrome (Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-like episodes), but it can also lead to type 2 diabetes, deafness, renal tubulopathy and/or cardiomyopathy. To identify pathogenic processes induced by this mutation, we compared global gene expression levels of muscle biopsies from affected and unaffected mutation carriers with controls. Gene expression changes were relatively subtle. In the a symptomatic group 200 transcripts were up- and 12 were down-regulated, whereas in the symptomatic group this was 15 and 52 respectively. In the a symptomatic group, oxidative phosphorylation (OXPHOS) complex I and IV genes were induced. Protein turnover and apoptosis were elevated, most likely due to the formation of dysfunctional and reactive oxygen species (ROS) damaged proteins. These processes returned to normal in symptomatic patients. Components of the complement system were upregulated in both groups, which might indicate muscle regeneration. Most likely, protein damage andOXPHOSdysfunction stimulate repair (protein regeneration) and metabolic adaptation (OXPHOS). In a symptomatic individuals these processes suffice to prevent the occurrence of symptoms. However, in affected individuals the repair process terminates, presumably because of excessive damage, and switches to muscle regeneration, as indicated by a stronger complement activation. This switch leaves increasingly damaged tissue in place and muscle pathology becomes manifest. Therefore, the expression of complement components might be a marker for the severity and progression of MELAS clinical course.