Center for Connective Tissue

Current research projects

Dissertations

Osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a syndromic disease of bone fragility and severe skeletal dysplasia which is primarily caused by genetic defects in collagen type I. Given the wide distribution of collagen in connective tissues, the patients also present blue sclera, dentinogenesis imperfecta, hearing loss and cardiovascular abnormalities. The genetic landscape of OI currently includes approximately 20 genes, 3 of which were discovered by our research team. In addtion we manage the intermational database for OI (The COL1A1 gene homepage – Global Variome shared LOVD)

OI is one of the most common skeletal dysplasias and only in the Netherlands at least 1000 patients exist. Despite its severity and high prevalence there is still no approved medication specific for OI. Patients are chronically treated with a combination of surgical interventions and off-label drugs.

To address this urgent unmet need, we are developing pharmacological and gene therapy strategies. By using a small molecule screening we have identified collagen-stimulating compounds which are are being validated in vivo. Pharmacological treatment also includes targeting of ER stress. In addition, our team works on the generation of iPSC-derived mesenchymal stem cells as part of an ex vivo gene therapy approach. Amsterdam UMC is a site of the international TOPAZ clinical trial (dr Marelise Eekhoff).

We also conduct research to extraskeletal features of OI which despite having a large impact on the quality of life of these patients, remain underinvestigated.

Osteoporosis

In 2013 we discovered mutations in PLS3 as a cause of monogenic osteoporosis (10.1056/NEJMoa1308223). In contrast to other osteoporosis genes that are related to the regulation of extracellular matrix or cell differentiation, PLS3 is an actin-bundling protein. Although several families have been since then reported, the function of PLS3 remains puzzling. We aim to uncover the mechanistic details of this perplexing gene with relevant osteocyte, osteoclast and osteoblast cell and animal models in which we investigate the role of PLS3 in bone tissue mechanosensing and homeostasis.

Fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP) is a devastating disease of irreversible heterotopic ossification in skeletal muscles and other connective tissues. No therapy exists to prevent or reverse this process which eventually becomes life-threatening. FOP typically progresses by episodes of inflammation which trigger heterotopic ossification in the background of mutations in ACVR1. The ACVR1 receptor regulates bone formation by bone morphogenetic protein signaling. In FOP, ACVR1 becomes reactive to Actinin A. The identification of Activin A as a driver of FOP heterotopic ossification has led to efforts of its targeting. However, little is known about the source of Activin A and its regulation during the maturation of the ossification lesion. By using FOP patient-derived cell models we aim to identify factors influencing Activin A production in FOP in order to potentially uncover additional disease targets. Amsterdam UMC is a site of the international clinical trials REGN2477 (antibody against Activin A) and STOPFOP (repositioning of saracatinib); dr Marelise Eekhoff.

Partiningrum, Dwi Lestari; Harumsari, Stefani; Cayami, Ferdy Kurniawan; Lestariningsih, L; Pals, Gerard; Faradz, Sultana MH; Clinical evaluation and mutation analysis in Indonesian autosomal dominant polycystic kidney disease. Pakistan Journal of Medical and Health Sciences 2019;13:908-913

Maugeri, A; Voorhoeve, E; Appelman-Dijkstra, NM; van Dijk, ATH; van Dijk, FS; Eekhoff, EMW; Elting, MW; van Haeringen, A; Harsevoort, A; Isrie, M; Diagnostic yield of NGS analysis of a panel of Osteogenesis imperfecta-related genes in 550 patients with Osteogenesis imperfecta,(early-onset) nonsyndromic osteoporosis and related disorders. European Journal of Human Genetics 2019;27:1293-1293

Cozijnsen, Luc; Plomp, Astrid S; Post, Jan G; Pals, Gerard; Bogunovic, Natalija; Yeung, Kak K; Niessen, Hans WM; Goumans, Marie‐José TH; Barge‐Schaapveld, Daniela QCM; Micha, Dimitra; Pathogenic effect of a TGFBR1 mutation in a family with Loeys–Dietz syndrome. Molecular genetics & genomic medicine 2019;7:e00943

Cayami, Ferdy K; Maugeri, Alessandra; Treurniet, Sanne; Setijowati, Eva D; Teunissen, Bernd P; Eekhoff, Elisabeth MW; Pals, Gerard; Faradz, Sultana M; Micha, Dimitra; The first family with adult osteogenesis imperfecta caused by a novel homozygous mutation in CREB3L1. Molecular genetics & genomic medicine 2019;7:e823

Botman, Esmée; Raijmakers, Pieter GHM; Yaqub, Maqsood; Teunissen, Bernd; Netelenbos, Coen; Lubbers, Wouter; Schwarte, Lothar A; Micha, Dimitra; Bravenboer, Nathalie; Schoenmaker, Ton; Evolution of heterotopic bone in fibrodysplasia ossificans progressiva: An [18F] NaF PET/CT study. Bone 2019;124:1-6

Pals, Gerard; Marfan syndrome, a review. Journal of Biomedicine and Translational Research 2018;4:33-40

Paff, Tamara; Kooi, Irsan E; Moutaouakil, Youssef; Riesebos, Elise; Sistermans, Erik A; Daniels, Hans JMA; Weiss, Janneke MM; Niessen, Hans HWM; Haarman, Eric G; Pals, Gerard; Diagnostic yield of a targeted gene panel in primary ciliary dyskinesia patients. Human mutation 2018;39:653-665

Meekel, Jorn P; Groeneveld, Menno E; Bogunovic, Natalija; Keekstra, Niels; Musters, René JP; Zandieh-Doulabi, Behrouz; Pals, Gerard; Micha, Dimitra; Niessen, Hans WM; Wiersema, Arno M; An in vitro method to keep human aortic tissue sections functionally and structurally intact. Scientific reports 2018;8:1-12

Groeneveld, Menno Evert; Bogunovic, Natalija; Musters, René John Philip; Tangelder, Geert Jan; Pals, Gerard; Wisselink, Willem; Micha, Dimitra; Yeung, Kak Khee; Betaglycan (TGFBR3) up-regulation correlates with increased TGF-β signaling in Marfan patient fibroblasts in vitro. Cardiovascular Pathology 2018;32:44-49

Eekhoff, E Marelise W; Netelenbos, J Coen; de Graaf, Pim; Hoebink, Max; Bravenboer, Nathalie; Micha, Dimitra; Pals, Gerard; de Vries, Teun J; Lammertsma, Adriaan A; Raijmakers, Pieter GHM; Flare‐up after maxillofacial surgery in a patient with fibrodysplasia ossificans progressiva: an [18F]‐NaF PET/CT study and a systematic review. JBMR plus 2018;2:55-58

Eekhoff, E Marelise W; Botman, Esmée; Netelenbos, J Coen; de Graaf, Pim; Bravenboer, Nathalie; Micha, Dimitra; Pals, Gerard; de Vries, Teun J; Schoenmaker, Ton; Hoebink, Max; [18F] NaF PET/CT scan as an early marker of heterotopic ossification in fibrodysplasia ossificans progressiva. Bone 2018;109:143-146

de Vries, Teun J; Schoenmaker, Ton; Micha, Dimitra; Hogervorst, Jolanda; Bouskla, Siham; Forouzanfar, Tim; Pals, Gerard; Netelenbos, Coen; Eekhoff, E Marelise W; Bravenboer, Nathalie; Periodontal ligament fibroblasts as a cell model to study osteogenesis and osteoclastogenesis in fibrodysplasia ossificans progressiva. Bone 2018;109:168-177

Bravenboer, Nathalie; Riesebos, Elise; Van Essen, Huib; Eekhoff, Marelise; Pals, Gerard; Micha, Dimitra; Upregulated Transforming Growth Factor Beta (TGF beta) Signaling in Osteoblast-like cells from Osteogenesis Imperfecta Patients. JOURNAL OF BONE AND MINERAL RESEARCH 2018;33:304-304

Yeung, Kak K; Bogunovic, Natalija; Keekstra, Niels; Beunders, Adriaan AM; Pals, Jorrit; van der Kuij, Kim; Overwater, Eline; Wisselink, Willem; Blankensteijn, Jan D; van Hinsbergh, Victor WM; Transdifferentiation of human dermal fibroblasts to smooth muscle‐like cells to study the effect of MYH11 and ACTA2 mutations in aortic aneurysms. Human mutation 2017;38:439-450

Paff, Tamara; Loges, Niki T; Aprea, Isabella; Wu, Kaman; Bakey, Zeineb; Haarman, Eric G; Daniels, Johannes MA; Sistermans, Erik A; Bogunovic, Natalija; Dougherty, Gerard W; Mutations in PIH1D3 cause X-linked primary ciliary dyskinesia with outer and inner dynein arm defects. The American Journal of Human Genetics 2017;100:160-168

Maharani, Nani; Setyawati, Amallia N; Rifqi, Sodiqur; Sungkar, Muhammad A; Pals, Gerard; Faradz, Sultana MH; AB081. Variable major phenotypes in familial Marfan syndrome in Indonesia: a case report. Annals of Translational Medicine 2017;5:

Franken, Romy; Teixido-Tura, Gisela; Brion, Maria; Forteza, Alberto; Rodriguez-Palomares, Jose; Gutierrez, Laura; Dorado, David Garcia; Pals, Gerard; Mulder, Barbara JM; Evangelista, Artur; Relationship between fibrillin-1 genotype and severity of cardiovascular involvement in Marfan syndrome. Heart 2017;103:1795-1799

Bogunovic, N; Musters, RJP; Pals, G; Wisselink, W; Blankensteijn, JD; Micha, D; Zandieh-Doulabi, B; Yeung, KK; Transdifferentiation of Human Dermal Fibroblasts into Smooth Muscle Like Cells: a Novel Method to Study the Effect of Pathogenic Variants in Aortic Aneurysms. Journal of Vascular Research 2017;54:23-24

Yeung, Kak Khee; Bogunovic, Natalija; Musters, Rene; Micha, Dimitra; Pals, Gerard; Wisselink, Willem; Blankensteijn, Jan D; Zandieh-Doulabi, Behrouz; PC224. Transdifferentiation of Dermal Fibroblasts to Smooth Muscle-Like Cells: A New Method to Study the Contractile Forces in the Aortic Aneurysm Wall. Journal of Vascular Surgery 2016;63:221S

Schoenmaker, Ton; Micha, Dimitra; Netelenbos, Coen; Pals, Gerard; Eekhoff, Marelise W; Bravenboer, Nathalie; Effects of TGF-[beta] inhibition on osteogenesis and osteoclastogenesis by periodontal ligament fibroblasts from patients with fibrodysplasia ossificans progressiva. 43rd Annual European Calcified Tissue Society Congress 2016;5:

Pals, Gerard; Molecular Genetics, Genetic Testing, Novel Genome Sequencing Technologies. Journal of the Medical Sciences (Berkala ilmu Kedokteran) 2016;48:

Milbradt, J; Hamann, N; Peters, M; Hupperich, K; Hoffmann, A; Heilig, J; Micha, D; Van Dijk, F; Mendoza-Ferreira, N; Hammerschmidt, M; PLASTIN 3: A NEW REGULATOR OF BONE STRUCTURE IN ZEBRAFISH, MICE AND HUMAN. OSTEOPOROSIS INTERNATIONAL 2016;27:S186-S186

Micha, Dimitra; Voermans, Elise; Eekhoff, Marelise EW; van Essen, Huib W; Zandieh-Doulabi, Behrouz; Netelenbos, Coen; Rustemeyer, Thomas; Sistermans, EA; Pals, Gerard; Bravenboer, Nathalie; Inhibition of TGFβ signaling decreases osteogenic differentiation of fibrodysplasia ossificans progressiva fibroblasts in a novel in vitro model of the disease. Bone 2016;84:169-180

Meekel, Jorn; Musters, Rene; Zandieh-Doulabi, Behrouz; Micha, Dimitra; Pals, Gerard; Wisselink, Willem; Blankensteijn, Jan D; Yeung, Kak Khee; PC226. Live Human Arterial Tissue Slices for Bench-Top Research on Pathophysiology of Aortic Aneurysms. Journal of Vascular Surgery 2016;63:222S

Franken, Romy; Groenink, Maarten; de Waard, Vivian; Feenstra, Helena MA; Scholte, Arthur J; van den Berg, Maarten P; Pals, Gerard; Zwinderman, Aeilko H; Timmermans, Janneke; Mulder, Barbara JM; Genotype impacts survival in Marfan syndrome. European heart journal 2016;37:3285-3290

den Hartog, Alexander W; Franken, Romy; van den Berg, Maarten P; Zwinderman, Aeilko H; Timmermans, Janneke; Scholte, Arthur J; de Waard, Vivian; Spijkerboer, Anje M; Pals, Gerard; Mulder, Barbara JM; The effect of losartan therapy on ventricular function in Marfan patients with haploinsufficient or dominant negative FBN1 mutations. Netherlands Heart Journal 2016;24:675-681

Paff, Tamara; Haarman, Eric; Daniels, Johannes MA; Nagelkerke, Ad; Pals, Gerard; The Diagnostic Yield Of A Novel Targeted-Exome Sequencing Kit In Dutch Primary Ciliary Dyskinesia Patients. D23. PEDIATRIC RARE DISEASES AND LUNG DEVELOPMENT 2015;:A5455-A5455

Paff, T; Haarman, E; Daniels, JMA; Nagelkerke, A; Pals, G; D23 PEDIATRIC RARE DISEASES AND LUNG DEVELOPMENT: The Diagnostic Yield Of A Novel Targeted-Exome Sequencing Kit In Dutch Primary Ciliary Dyskinesia Patients. American Journal of Respiratory and Critical Care Medicine 2015;191:1

Monroe, Glen R; Harakalova, Magdalena; van der Crabben, Saskia N; Majoor‐Krakauer, Danielle; Bertoli‐Avella, Aida M; Moll, Frans L; Oranen, Björn I; Dooijes, Dennis; Vink, Aryan; Knoers, Nine V; Familial Ehlers‐Danlos syndrome with lethal arterial events caused by a mutation in COL5A1. American Journal of Medical Genetics Part A 2015;167:1196-1203

Micha, Dimitra; Guo, Dong‐chuan; Hilhorst‐Hofstee, Yvonne; van Kooten, Fop; Atmaja, Dian; Overwater, Eline; Cayami, Ferdy K; Regalado, Ellen S; van Uffelen, René; Venselaar, Hanka; SMAD2 mutations are associated with arterial aneurysms and dissections. Human mutation 2015;36:1145-1149

Franken, Romy; Radonic, Teodora; den Hartog, Alexander W; Groenink, Maarten; Pals, Gerard; van Eijk, Marco; Lutter, Rene; Mulder, Barbara JM; Zwinderman, Aeilko H; de Waard, V; The revised role of TGF-β in aortic aneurysms in Marfan syndrome. Netherlands Heart Journal 2015;23:116-121

Franken, Romy; den Hartog, Alexander W; Radonic, Teodora; Micha, Dimitra; Maugeri, Alessandra; van Dijk, Fleur S; Meijers-Heijboer, Hanne E; Timmermans, Janneke; Scholte, Arthur J; van den Berg, Maarten P; Beneficial outcome of losartan therapy depends on type of FBN1 mutation in Marfan syndrome. Circulation: Cardiovascular Genetics 2015;8:383-388

Franken, R; Groenink, M; de Waard, V; Feenstra, H; Scholte, AJ; van den Berg, M; Pals, G; Zwinderman, AH; Timmermans, J; Mulder, BJM; Genotype impacts survival in marfan syndrome. 2015;:

Eekhoff, Elisabeth Marelise; Van, Es Robert; Van, Schie Annelies; Raijmakers, Pieter; Jan-Paul, Klein; Micha, Dimitra; Pals, Gerard; Bravenboer, Nathalie; Netelenbos, Coen; A Maxillo-Facial Operation in a Patient with Fibrodysplasia Ossificans Progressiva (FOP): are we Ready for it?. ECTS-IBMS2015 2015;1:

den Hartog, Alexander W; Franken, Romy; Zwinderman, Aeilko H; Timmermans, Janneke; Scholte, Arthur J; van den Berg, Maarten P; de Waard, Vivian; Pals, Gerard; Mulder, Barbara JM; Groenink, Maarten; The risk for type B aortic dissection in Marfan syndrome. Journal of the American College of Cardiology 2015;65:246-254

Cancrinus, Ernst; Hoksbergen, Arjan WJ; Pals, Gerard J; Wisselink, Willem; Yeung, Kak Khee; Loeys-Dietz syndrome: aortic dissections and aneurysms. Nederlands tijdschrift voor geneeskunde 2015;159:A8342

Bravenboer, Nathalie; Micha, Dimitra; Triffit, James T; Bullock, Alex N; Ravazollo, Roberto; Bocciardi, Renata; Di Rocco, Maja; Netelenbos, J Coen; Ten Dijke, Peter; Sánchez-Duffhues, Gonzalo; Clinical utility gene card for: fibrodysplasia ossificans progressiva. European Journal of Human Genetics 2015;23:1431-1431

Ramnath, NWM; Pals, G; d Majoor-Krakauer, JW; Fibulin-4 mutation analysis of patients with thoracic and abdominal aortic disease. Molecular Pathogenesis of Fibulin-4 Associated Aortic Aneurysms 2014;:133

Paff, Tamara; de Fluiter, Kirsten; Sinkeldam, Jerica; Daniels, Johannes; Postmus, Pieter; Pals, Gerard; Haarman, Eric; Detection of primary ciliary dyskinesia by hand-held tidal breathing nasal nitric oxide measurements in a tertiary referral population. European Respiratory Journal 2014;44:

Paff, Tamara; Daniels, Johannes; Pals, Gerard; Haarman, Eric G; Primary ciliary dyskinesia: from diagnosis to molecular mechanisms. Journal of pediatric genetics 2014;3:115-127

Onoufriadis, Alexandros; Shoemark, Amelia; Munye, Mustafa M; James, Chela T; Schmidts, Miriam; Patel, Mitali; Rosser, Elisabeth M; Bacchelli, Chiara; Beales, Philip L; Scambler, Peter J; Combined exome and whole-genome sequencing identifies mutations in ARMC4 as a cause of primary ciliary dyskinesia with defects in the outer dynein arm. Journal of medical genetics 2014;51:61-67

Nota, Benjamin; Ndika, Joseph DT; van de Kamp, Jiddeke M; Kanhai, Warsha A; van Dooren, Silvy JM; van de Wiel, Mark A; Pals, Gerard; Salomons, Gajja S; RNA Sequencing of Creatine Transporter (SLC 6 A 8) Deficient Fibroblasts Reveals Impairment of the Extracellular Matrix. Human mutation 2014;35:1128-1135

Franken, Romy; Heesterbeek, Thomas J; de Waard, Vivian; Zwinderman, Aeilko H; Pals, Gerard; Mulder, Barbara JM; Groenink, Maarten; Diagnosis and genetics of Marfan syndrome. Expert opinion on orphan drugs 2014;2:1049-1062

Franken, R; den Hartog, AW; Radonic, T; Timmermans, J; Scholte, AJ; van den Berg, MP; Groenink, M; Mulder, BJM; de Waard, V; Pals, G; Enhanced beneficial outcome of losartan therapy in Marfan patients with FBN1 haploinsufficiency mutations. 2014;:

den Hartog, AW; Franken, R; Zwinderman, AH; Timmermans, J; de Waard, V; van den Berg, MP; Scholte, AHJ; Pals, G; Mulder, BJM; Groenink, M; The risk of type B aortic dissection in Marfan syndrome. 2014;:

Bravenboer, Nathalie; Micha, Dimitra; van Essen, Huib; Netelenbos, Coen; Pals, Gerard; Eekhoff, Marelise; High Osteogenic Potential of fibroblast from FOP Patients. JOURNAL OF BONE AND MINERAL RESEARCH 2014;29:S422-S422

Bravenboer, Nathalie; Micha, Dimitra; Netelenbos, Coen; Eekhoff, Marelise; Pals, Gerard; Osteogenic differentiation of fibroblast derived from patients with fybrodisplasia ossificans progressiva. European Calcified Tissue Society Congress 2014 2014;3:

Aalberts, JJJ; Schuurman, AG; Pals, G; Hamel, BJC; Bosman, G; Hilhorst-Hofstee, Y; Barge-Schaapveld, DQCM; Mulder, BJM; van den Berg, MP; van Tintelen, JP; Recurrent and founder mutations in the Netherlands: Extensive clinical variability in Marfan syndrome patients with a single novel recurrent fibrillin-1 missense mutation. Founder mutations in inherited cardiac diseases in the Netherlands 2014;:89-94

Aalberts, Jan JJ; van Tintelen, J Peter; Meijboom, Lilian J; Polko, Annette; Jongbloed, Jan DH; van der Wal, Henriette; Pals, Gerard; Osinga, Jan; Timmermans, Janneke; De Backer, Julie; Relation between genotype and left-ventricular dilatation in patients with Marfan syndrome. Gene 2014;534:40-43

Zillikens, Carola; van Dijk, Fleur; Micha, Dimitra; Riessland, Markus; Marcelis, Carlo LM; Christine, E; Milbradt, Janine; Franken, Anton; Harsevoort, Arjan; Lichtenbelt, Klaske; A genetic cause of X-linked Osteoporosis and Fractures. Journal of Bone and Mineral Research 2013;28:

van Dijk, Fleur S; Zillikens, M Carola; Micha, Dimitra; Riessland, Markus; Marcelis, Carlo LM; de Die-Smulders, Christine E; Milbradt, Janine; Franken, Anton A; Harsevoort, Arjan J; Lichtenbelt, Klaske D; PLS3 mutations in X-linked osteoporosis with fractures. New England Journal of Medicine 2013;369:1529-1536

Van Dijk, Fleur S; Dalgleish, Raymond; Malfait, Fransiska; Maugeri, Alessandra; Rusinska, Agnieszka; Semler, Oliver; Symoens, Sofie; Pals, Gerard; Clinical utility gene card for: osteogenesis imperfecta. European Journal of Human Genetics 2013;21:1-4

Schwarze, Ulrike; Cundy, Tim; Pyott, Shawna M; Christiansen, Helena E; Hegde, Madhuri R; Bank, Ruud A; Pals, Gerard; Ankala, Arunkanth; Conneely, Karen; Seaver, Laurie; Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen. Human molecular genetics 2013;22:1-17

Paff, Tamara; van der Schee, MP; Daniels, Johannes MA; Pals, Gerard; Postmus, Piet E; Sterk, Peter J; Haarman, Eric G; Exhaled molecular profiles in the assessment of cystic fibrosis and primary ciliary dyskinesia. Journal of Cystic Fibrosis 2013;12:454-460

Paff, Tamara; Onoufriadis, Alexandros; Antony, Dinu; Shoemark, Amelia; Micha, Dimitra; Kuyt, Bertus; Schmidts, Miriam; Petridi, Stavroula; Dankert-Roelse, Jeannette; Haarman, Eric; Splice Site Mutations In The Outer Dynein Arm Docking Complex Gene CCDC114 Cause Primary Ciliary Dyskinesia With Apparent Normal Fertility. A96. A TALE OF TWO RARE LUNG DISEASES IN PEDIATRICS: PRIMARY CILIARY DYSKINESIA AND PULMONARY HYPERTENSION 2013;:A2083-A2083

Paff, Tamara; Haarman, Eric; Daniels, Hans; Moutaouakil, Youssef; Micha, Dimitra; Massink, Maarten; Postmus, Piet; Pals, Gerard; Evaluation of gene expression during in vitro ciliogenesis to search for novel candidate genes in primary ciliary dyskinesia. 2013;:

Paff, T; Onoufriadis, A; Anthony, D; Shoemark, A; Micha, D; Kuyt, B; Schmidts, M; Petridi, S; Dankert-Roelse, JE; Haarman, EG; Mutation in the CCDC114 gene causes Primary Ciliary Dyskinesia with normal fertility in the isolated Volendam population. Tijdschrift voor Kindergeneeskunde 2013;1:92-92

Onoufriadis, Alexandros; Paff, Tamara; Antony, Dinu; Shoemark, Amelia; Micha, Dimitra; Kuyt, Bertus; Schmidts, Miriam; Petridi, Stavroula; Dankert-Roelse, Jeanette E; Haarman, Eric G; Splice-site mutations in the axonemal outer dynein arm docking complex gene CCDC114 cause primary ciliary dyskinesia. The American Journal of Human Genetics 2013;92:88-98

Hilhorst‐Hofstee, Y; Scholte, AJHA; Rijlaarsdam, MEB; Van Haeringen, A; Kroft, LJ; Reijnierse, M; Ruivenkamp, CAL; Versteegh, MIM; Pals, G; Breuning, MH; An unanticipated copy number variant of chromosome 15 disrupting SMAD3 reveals a three‐generation family at serious risk for aortic dissection. Clinical Genetics 2013;83:337-344

Harakalova, Magdalena; Van Der Smagt, Jasper; De Kovel, Carolien GF; Van’t Slot, Ruben; Poot, Martin; Nijman, Isaac J; Medic, Jelena; Joziasse, Irene; Deckers, Jaap; Roos-Hesselink, Jolien W; Incomplete segregation of MYH11 variants with thoracic aortic aneurysms and dissections and patent ductus arteriosus. European Journal of Human Genetics 2013;21:487-493

Vreeburg, M; de Vos-Houben, J; Schouten, M; Weiss, J; Pals, G; Maugeri, A; Robben, S; Detisch, Y; van Eijsden-Besseling, MDF; Verbunt, AMCF; The benign joint hypermobility syndrome: guidelines for diagnosis and management. 2012;:

Van Dijk, Fleur S; Byers, Peter H; Dalgleish, Raymond; Malfait, Fransiska; Maugeri, Alessandra; Rohrbach, Marianne; Symoens, Sofie; Sistermans, Erik A; Pals, Gerard; EMQN best practice guidelines for the laboratory diagnosis of osteogenesis imperfecta. European Journal of Human Genetics 2012;20:11-19

van de Laar, Ingrid MBH; van der Linde, Denise; Oei, Edwin HG; Bos, Pieter K; Bessems, Johannes H; Bierma-Zeinstra, Sita M; van Meer, Belle L; Pals, Gerard; Oldenburg, Rogier A; Bekkers, Jos A; Phenotypic spectrum of the SMAD3-related aneurysms–osteoarthritis syndrome. Journal of medical genetics 2012;49:47-57

Setijowati, ED; Van Dijk, FS; Cobben, JM; Van Rijn, RR; Sistermans, EA; Faradz, SMH; Kawiyana, S; Pals, G; A novel homozygous 5 bp deletion in FKBP10 causes clinically Bruck syndrome in an Indonesian patient. European journal of medical genetics 2012;55:17-21

Radonic, Teodora; Groenink, Maarten; Ruigrok, Ynte M; de Witte, Piet; Rinkel, Gabriel JE; Kleinloog, Rachel; Timmermans, Janneke; Kempers, Marlies; Scholte, Arthur J; Hilhorst-Hofstee, Yvonne; Genetic variation in inflammatory genes contributes to the severity of the vascular disease in Marfan patients. Novel diagnostic and therapeutic targets in Marfan syndrome 2012;:115

Radonic, Teodora; de Witte, Piet; Groenink, Maarten; Pals, Gerard; van Eijk, Marco; Lutter, Rene; van de Pol, Marianne A; Timmermans, Janneke; Kempers, Marlies; Scholte, Arthur J; Losartan therapy has prominent but highly variable effects on circulating TGF-β in Marfan patients. Novel diagnostic and therapeutic targets in Marfan syndrome 2012;:135

Radonic, Teodora; de Witte, Piet; Groenink, Maarten; de Waard, Vivian; Lutter, Rene; van Eijk, Marco; Jansen, Marnix; Timmermans, Janneke; Kempers, Marlies; Scholte, Arthur J; Inflammation aggravates disease severity in Marfan syndrome patients. PloS one 2012;7:e32963

Paff, Tamara; van der Schee, Marc P; Daniels, Johannes MA; Pals, Gerard; Postmus, Pieter E; Sterk, Peter J; Haarman, Eric G; Exhaled Molecular Profiles In The Diagnosis Of Cystic Fibrosis And Primary Ciliary Dyskinesia. A105. EVALUATION OF PEDIATRIC LUNG DISEASES 2012;:A2345-A2345

Paff, Tamara; Haarman, Eric G; Pals, Gerard; Postmus, Pieter E; Daniels, Johannes MA; Bacterial Pathogens In The Airways Of Patients With Primary Ciliary Dyskinesia. C108. PEDIATRIC CYSTIC FIBROSIS AND PRIMARY CILIARY DYSKINESIA 2012;:A5279-A5279

Klaassens, M; Reinstein, E; Hilhorst‐Hofstee, Y; Schrander, JJP; Malfait, Fransiska; Staal, H; ten Have, LC; Blaauw, J; Roggeveen, HCJ; Krakow, D; Ehlers–Danlos arthrochalasia type (VIIA–B)–expanding the phenotype: from prenatal life through adulthood. Clinical genetics 2012;82:121-130

Hilhorst-Hofstee, Y; Scholte, AJHA; Rijlaarsdam, MEB; van Haeringen, A; Kroft, LJ; Reijnierse, M; Ruivenkamp, CAL; Versteegh, MIM; Pals, G; Breuning, MH; An unanticipated copy number variant ofáchromosome 15 disrupting SMAD3 reveals a three-generation family at serious risk for aortic dissection.. 2012;:

Gentile, Filomena Valentina; Zuntini, Monia; Parra, Alessandro; Battistelli, Luca; Pandolfi, Martina; Pals, Gerard; Sangiorgi, Luca; Validation of a quantitative PCR–high‐resolution melting protocol for simultaneous screening of COL1A1 and COL1A2 point mutations and large rearrangements: Application for diagnosis of osteogenesis imperfecta. Human mutation 2012;33:1697-1707

Franken, Romy; Radonic, Teodora; den Hartog, Alexander; Ruigrok, Ynte M; Groenink, Maarten; de Witte, Piet; Timmermans, Janneke; Scholte, Arthur; Pals, Gerard; Van Den Berg, Maarten; Inflammatory genes are associated with severity of aortic root aneurysm progression in patients with Marfan syndrome: Journal of the American College of Cardiology 2012;59:E834

Franken, Romy; den Hartog, Alexander W; Singh, Michael; Pals, Gerard; Zwinderman, Aeilko H; Groenink, Maarten; Mulder, Barbara JM; Marfan syndrome: Progress report. Progress in Pediatric Cardiology 2012;34:9-14

Franken, R; Radonic, T; Den Hartog, AW; Groenink, M; Timmermans, J; Scholte, AJHA; Van Den Berg, M; Pals, G; Mulder, BJM; Zwinderman, AH; Losartan therapy has prominent but highly variable effects on circulating TGF-beta in Marfan patients. European Heart journal 2012;33:503-503

Burger, Nicole B; Einarsson, Jon I; Brölmann, Henricus AM; Vree, Florentien EM; McElrath, Thomas F; Huirne, Judith AF; Preconceptional laparoscopic abdominal cerclage: a multicenter cohort study. American journal of obstetrics and gynecology 2012;207:273. e1-273. e12

van Dijk, Fleur S; Nikkels, Peter GJ; den Hollander, Nicolette S; Nesbitt, Isabel M; van Rijn, Rick R; Cobben, Jan M; Pals, Gerard; Lethal/severe osteogenesis imperfecta in a large family: a novel homozygous LEPRE1 mutation and bone histological findings. Pediatric and Developmental Pathology 2011;14:228-234

van Dijk, Fleur S; Cobben, Jan M; Kariminejad, Ariana; Maugeri, Alessandra; Nikkels, Peter GJ; van Rijn, Rick R; Pals, Gerard; Osteogenesis imperfecta: a review with clinical examples. Molecular syndromology 2011;2:1-20

van de Laar, Ingrid MBH; Oldenburg, Rogier A; Pals, Gerard; Roos-Hesselink, Jolien W; de Graaf, Bianca M; Verhagen, Judith MA; Hoedemaekers, Yvonne M; Willemsen, Rob; Severijnen, Lies-Anne; Venselaar, Hanka; Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nature genetics 2011;43:121-126

Hilhorst-Hofstee, Yvonne; Hamel, Ben CJ; Verheij, Joke BGM; Rijlaarsdam, Marry EB; Mancini, Grazia MS; Cobben, Jan M; Giroth, Cindy; Ruivenkamp, Claudia AL; Hansson, Kerstin BM; Timmermans, Janneke; The clinical spectrum of complete FBN1 allele deletions. European journal of human genetics 2011;19:247-252

Van Dijk, FS; Pals, G; Van Rijn, RR; Nikkels, PGJ; Cobben, JM; Classification of osteogenesis imperfecta revisited. European journal of medical genetics 2010;53:1-5

van Dijk, Fleur S; Huizer, Margriet; Kariminejad, Ariana; Marcelis, Carlo L; Plomp, Astrid S; Terhal, Paulien A; Meijers-Heijboer, Hanne; Weiss, Marjan M; van Rijn, Rick R; Cobben, Jan M; Complete COL1A1 allele deletions in osteogenesis imperfecta. Genetics in Medicine 2010;12:736-741

van Dijk, Fleur S; Cobben, Jan M; Pals, Gerard; Osteogenesis imperfecta, normal collagen folding, and lack of cyclophilin B. New England Journal of Medicine 2010;362:1940-1941

Klaassens, M; Hilhorst-Hofstee, Y; Staal, H; Speth, L; Schrander, J; Pals, G; De Paepe, A; Malfait, F; Schrander-Stumpel, C; 815 Neonatal Presentation of Ehlers-Danlos Type Vii: Diagnostic Considerations. Pediatric Research 2010;68:410-410

Hilhorst‐Hofstee, Yvonne; Rijlaarsdam, Marry EB; Scholte, Arthur JHA; Swart‐van den Berg, Marietta; Versteegh, Michel IM; van der Schoot‐van Velzen, Iris; Schäbitz, Hans‐Joachim; Bijlsma, Emilia K; Baars, Marieke J; Kerstjens‐Frederikse, Wilhelmina S; The clinical spectrum of missense mutations of the first aspartic acid of cbEGF‐like domains in fibrillin‐1 including a recessive family. Human mutation 2010;31:E1915-E1927

Hilhorst-Hofstee, Yvonne; Hamel, Ben Jc; Verheij, Joke BGM; Rijlaarsdam, Marry EB; Mancini, Grazia Ms; Cobben, Jan Maarten; Giroth, Cindy; Ruivenkamp, Claudia; Hansson, Kerstin BM; Timmermans, Janneke; The clinical spectrum of complete allele deletions. 2010;:

Aalberts, JJJ; Schuurman, AG; Pals, G; Hamel, BJC; Bosman, GJCGM; Hilhorst-Hofstee, Y; Barge-Schaapveld, DQCM; Mulder, BJM; van den Berg, MP; van Tintelen, JP; recurrent and founder mutations in the netherlands. Netherlands Heart Journal 2010;18:85-89

Aalberts, JJJ; Schuurman, AG; Pals, G; Hamel, BJC; Bosman, G; Hilhorst-Hofstee, Y; Barge-Schaapveld, DQCM; Mulder, BJM; van den Berg, MP; van Tintelen, JP; FoUnder mutations in the netherlands. Netherlands Heart Journal 2010;18:31

Aalberts, Jan JJ; Schuurman, Agnes G; Pals, Gerard; Hamel, Ben JC; Bosman, Gerdien; Hilhorst-Hofstee, Yvonne; Barge-Schaapveld, Daniela QCM; Mulder, Barbara JM; van den Berg, Maarten P; van Tintelen, J Peter; extensive clinical variability in Marfan syndrome patients with a single novel recurrent fibrillin-1 missense mutation. Neth Heart J 2010;18:85-89

Van Tintelen, Peter; Meijboom, Lilian J; Jongbloed, Jan D; Pals, Gerard; Timmermans, Janneke; De Backer, Julie; Hofstra, Robert M; Mulder, Barbara J; van den Berg, Maarten P; Relation Between Genotype and Left-Ventricular Dilatation in Patients With Marfan Syndrome. Circulation 2009;120:

Van Dijk, FS; Hamel, BC; Hilhorst-Hofstee, Y; Mulder, BJM; Timmermans, J; Pals, G; Cobben, JM; Compound-heterozygous Marfan syndrome. European journal of medical genetics 2009;52:1-5

van Dijk, Fleur S; Nesbitt, Isabel M; Zwikstra, Eline H; Nikkels, Peter GJ; Piersma, Sander R; Fratantoni, Silvina A; Jimenez, Connie R; Huizer, Margriet; Morsman, Alice C; Cobben, Jan M; PPIB mutations cause severe osteogenesis imperfecta. The American Journal of Human Genetics 2009;85:521-527

Van Dijk, Fleur S; Nesbitt, Isabel M; Nikkels, Peter GJ; Dalton, Ann; Bongers, Ernie MHF; Van De Kamp, Jiddeke M; Hilhorst-Hofstee, Yvonne; Den Hollander, Nicolette S; Lachmeijer, Augusta MA; Marcelis, Carlo L; CRTAP mutations in lethal and severe osteogenesis imperfecta: the importance of combining biochemical and molecular genetic analysis. European journal of human genetics 2009;17:1560-1569

Maharani, Nani; Faradz, Sultana MH; Pals, Gerald; Hamel, Ben CJ; Analysis of the tgfbr1 gene as a candidate gene in marfan syndrome and related disorders patients, negative for fbn1 and tgfbr2 mutations. 2009;:

Maharani, N; Setyawati, AN; Rifqi, S; Sungkar, MA; Purwanti, A; Faradz, Sultana MH; Pals, G; Marfan Syndrome in Semarang: report of two cases. 2009;:

Dankert-Roelse, JE; Vernooij-van Langen, AMM; Loeber, JG; Elvers, LH; Triepels, RH; Gille, JJP; Pals, G; van den Akker-van Marle, ME; van der Ploeg, CPB; van der Pal, SM; Cystic fibrosis hielprik onderzoek bij pasgeborenen in Nederland: de Chopin studie eindrapport. 2009;:

Ameziane, Najim; Chen, Fei; Waisfisz, Quinten; Oostra, Anneke B; Grenman, Seija; Zhang, Kejian; Xia, Bing; Leemans, René C; Pals, Gerard; de Winter, Johan P; Evidence for FA/BRCA pathway impairment in a proportion of squamous cell carcinomas. Fanconi anemia pathway defects in sporadic cancer 2009;:133

van Diest, Paul J; Moelans, CB; Purnomosari, D; Pals, G; de Weger, RA; Invasive Breast Cancer: Overexpression of HER-2 Determined by Immunohistochemistry and Multiplex Ligation-Dependent Probe Amplification. Methods of Cancer Diagnosis, Therapy and Prognosis 2008;:291-304

Jimenez, Sergio A; Rosenbloom, Joel; Angiotensin II blockade in Marfan’s syndrome.. The New England journal of medicine 2008;359:1732

Hilhorst-Hofstee, Yvonne; Kroft, Lucia JM; Pals, Gerard; van Vugt, Jeroen PP; Overweg-Plandsoen, Wouterina CG; Intracranial hypertension in 2 children with marfan syndrome. Journal of child neurology 2008;23:954-955

Brooke, Benjamin S; Habashi, Jennifer P; Judge, Daniel P; Patel, Nishant; Loeys, Bart; Dietz III, Harry C; Angiotensin II blockade and aortic-root dilation in Marfan’s syndrome. New England Journal of Medicine 2008;358:2787-2795

Ameziane, Najim; Errami, Abdellatif; Léveillé, France; Fontaine, Chantal; de Vries, Yne; van Spaendonk, Rosalina ML; de Winter, Johan P; Pals, Gerard; Joenje, Hans; Genetic subtyping of Fanconi anemia by comprehensive mutation screening. Human mutation 2008;29:159-166

Ameziane, Najim; Chen, Fei; Medhurst, Annette; Waisfisz, Quinten; Grenman, Seija; Pals, Gerard; de Winter, Johan; Brakenhoff, Ruud; Joenje, Hans; Evidence for FA-BRCA pathway defects in a proportion of squamous cell carcinoma. 2008;:

Aalberts, Jan JJ; van den Berg, Maarten P; Bergman, Jorieke EH; du Marchie Sarvaas, Gideon J; Post, Jan G; van Unen, Hans; Pals, Gerard; Boonstra, Piet W; van Tintelen, J Peter; The many faces of aggressive aortic pathology: Loeys-Dietz syndrome. Netherlands Heart Journal 2008;16:299-304

Xia, Bing; Dorsman, Josephine C; Ameziane, Najim; De Vries, Yne; Rooimans, Martin A; Sheng, Qing; Pals, Gerard; Errami, Abdellatif; Gluckman, Eliane; Llera, Julian; Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nature genetics 2007;39:159-161

Wahyono, A; Aryandono, T; Pals, G; Van Diest, PJ; Histopathological Features of Early Onset Indonesian Breast Cancer Pointing to Brca1/2 Germline Mutations. Berita Kedokteran Masyarakat 2007;23:97

van Diest, PJ; Pals, G; A novel rapid and sensitive BRCA1/2 mutation detection method based on pooled DGGE and targeted sequencing. Journal of clinical pathology 2007;60:478-478

Purnomosari, Dewajani; Pals, Gerard; Wahyono, Artanto; Aryandono, Teguh; Manuaba, Tjakra W; Haryono, Samuel J; Van Diest, Paul J; BRCA1 and BRCA2 germline mutation analysis in the Indonesian population. Breast cancer research and treatment 2007;106:297-304

Purnomosari, D; Wahyono, A; Aryandono, T; Pals, G; van Diest, PJ; High throughput analysis of gene amplification of 27 genes in invasive breast cancer by MLPA. Molecular analysis of early onset Indonesian breast cancer 2007;:105

Purnomosari, D; Ameziane, N; Wahyono, A; Aryandono, T; Meijer, GA; Pals, G; van Diest, PJ; High throughput analysis of promoter hypermethylation status of 22 tumor suppressor genes in invasive breast cancer. Molecular analysis of early onset Indonesian breast cancer 2007;:91

Pol, RA; Kurvers, HAJM; Verheij, JBGM; Pals, G; van der Wal, AM; Boers, J; Jörning, PJG; Spontaneous Non-traumatic rupture of a Non-aneurysmatic infrarenal abdominal aorta in a 10-year old girl without histological evidence of connective tissue or autoimmune disease: a case report. EJVES Extra 2007;13:9-12

Oosterkamp, MJ; Mulders, J; Poutsma, A; Konst, AAM; Lachmeijer, AMA; Pals, G; Blankenstein, MA; Oudejans, CBM; Genetics of HELLP syndrome. Placenta 2007;28:A63-A63

Kalba, Reinhard; Neveling, Kornelia; Hoehn, Holger; Schneider, Hildegard; Linka, Yvonne; Batishb, Sat Dev; Hunt, Curtis; Berwick, Marianne; Callén, Elsa; Surrallés i Calonge, Jordi; Hypomorphic Mutations in the Central Fanconi Anemia Gene FANCD2 Sustain a Significant Group of FA-D2 Patients with Severe Phenotype. Running title: FA-D2 phenotype and FANCD2 mutations. American journal of human genetics 2007;80:0895-910

Kalb, Reinhard; Neveling, Kornelia; Hoehn, Holger; Schneider, Hildegard; Linka, Yvonne; Batish, Sat Dev; Hunt, Curtis; Berwick, Marianne; Callén, Elsa; Surrallés, Jordi; Hypomorphic mutations in the gene encoding a key Fanconi anemia protein, FANCD2, sustain a significant group of FA-D2 patients with severe phenotype. The American Journal of Human Genetics 2007;80:895-910

Dorsman, Josephine C; Levitus, Marieke; Rockx, Davy; Rooimans, Martin A; Oostra, Anneke B; Haitjema, Anneke; Bakker, Sietske T; Steltenpool, Jûrgen; Schuler, Dezsö; Mohan, Sheila; Identification of the Fanconi anemia complementation group I gene, FANCI. Analytical Cellular Pathology 2007;29:211-218

de Vries, Bert BA; Pals, Gerard; Odink, Roelof; Hamel, Ben CJ; Homozygosity for a FBN1 missense mutation: clinical and molecular evidence for recessive Marfan syndrome. European journal of human genetics 2007;15:930-935

Towards better understanding of the pathophysiology of aortic aneurysms: the role of smooth muscle cells

Investigator: N. Bogunovic

Promotors: J. Blankensteijn, P.L. Hordijk

Co-promotors: K.K. Yeung, D. Micha

Award date: 21 Oct 2020

Hypomyelination with tooth and bone involvement: New insights: Brain MR imaging and in vitro models

Investigator: F.K. Cayami

Promotors: M. van der Knaap

Co-promotors: N.I. Wolf, D. Micha

Award date: 20 Feb 2018