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Centrum voor Bindweefselonderzoek

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Research

The Center for Connective Tissue Disorders in the Clinical Genetics department specialises in the study of osteogenesis imperfecta and hereditary osteoporosis. Osteogenesis imperfecta patients experience frequent bone fractures as a result of bone fragility arising from mutations that affect collagen regulation. We aim to identify new genetic causes and unravel the mechanism by which these lead to disease presentation. Based on this knowledge we aim to develop novel approaches for effective therapy. We have developed a novel method of osteogenic transdifferentiation by which osteoblasts can be derived from patient dermal fibroblasts. We are using these cells as a platform for the testing of pharmaceuticals.

We also focus on fibrodysplasia ossificans progressiva, a disorder of severe heterotopic ossification. Our research on understanding of its mechanism aims the development of much needed therapeutic interventions.

Our research extends to the study of aneurysms as part of hereditary syndromes. These include the Marfan syndrome, Loeys-Dietz syndrome and Ehlers-Danlos syndrome.

The Center for Connective Tissue Disorders is embedded in the Amsterdam Movement Sciences (AMS) and Amsterdam Cardiovascular Sciences (ACS).

Members 

Dimitra Micha
Principal investigator
d.micha@vumc.nl

Gerard Pals
Senior scientist
g.pals@vumc.nl

Ferdy K Cayami
PhD student
f.cayami@vumc.nl

Natalija Bogunovic
PhD student
n.bogunovic@vumc.nl

Elise Riesebos
Research technician
e.riesebos@vumc.nl

Publications

2017
T. J. de Vries, T. Schoenmaker, D. Micha, J. Hogervorst, S. Bouskla, T. Forouzanfar, G. Pals, C. Netelenbos, E. M. W. Eekhoff and N. Bravenboer, Periodontal ligament fibroblasts as a cell model to study osteogenesis and osteoclastogenesis in fibrodysplasia ossificans progressiva., Bone, 2017 July.

E.M. Eekhoff, J.C. Netelenbos, P. de Graaf, M. Hoebink, N. Bravenboer, D. Micha, G. Pals, T.J. de Vries, A.A. Lammertsma, P.G.H.M. Raijmakers, R.J.J. van Es, Flare-up after Maxillofacial Surgery in a Patient with Fibrodysplasia Ossificans Progressiva: an [18F]-NaF PET/CT Study and a Systematic Review., J. Bone Miner. Res. Plus., 2017 May.

R. Franken, G. Teixido-Tura, M. Brion, A. Forteza, J. Rodriguez-Palomares, L. Gutierrez, D. Garcia Dorado, G. Pals, B. J. Mulder and A. Evangelista, Relationship between fibrillin-1 genotype and severity of cardiovascular involvement in Marfan syndrome., Heart, 2017 May.

S. Vrij-van den Bos, J. Hol, R. La Piana, I. Harting, A. Vanderver, F. Barkhof, F. Cayami, W. van Wieringen, P. Pouwels, M. van der Knaap, G. Bernard and N. Wolf, 4H Leukodystrophy: A Brain Magnetic Resonance Imaging Scoring System., Neuropediatrics, 2017, 48, 152-160.

K. K. Yeung, N. Bogunovic, N. Keekstra, A. A. M. Beunders, J. Pals, K. van der Kuij, E. Overwater, W. Wisselink, J. D. Blankensteijn, V. W. M. van Hinsbergh, R. J. P. Musters, G. Pals, D. Micha and B. Zandieh-Doulabi, Transdifferentiation of Human Dermal Fibroblasts to Smooth Muscle-Like Cells to Study the Effect of MYH11 and ACTA2 Mutations in Aortic Aneurysms., Hum. Mutat., 2017, 38, 439-450.

T. Paff, N. T. Loges, I. Aprea, K. Wu, Z. Bakey, E. G. Haarman, J. M. A. Daniels, E. A. Sistermans, N. Bogunovic, G. W. Dougherty, I. M. Hoben, J. Grosse-Onnebrink, A. Matter, H. Olbrich, C. Werner, G. Pals, M. Schmidts, H. Omran and D. Micha, Mutations in PIH1D3 Cause X-Linked Primary Ciliary Dyskinesia with Outer and Inner Dynein Arm Defects., Am. J. Hum. Genet., 2017, 100, 160-168.

Demirdas, E. Dulfer, L. Robert, M. Kempers, D. van Beek, D. Micha, B. G. van Engelen, B. Hamel, J. Schalkwijk, B. Loeys, A. Maugeri and N. C. Voermans, Recognizing the tenascin-X deficient type of Ehlers-Danlos syndrome: a cross-sectional study in 17 patients., Clin. Genet., 2017, 91, 411-425.

2016
R. Franken, M. Groenink, V. de Waard, H. M. A. Feenstra, A. J. Scholte, M. P. van den Berg, G. Pals, A. H. Zwinderman, J. Timmermans and B. J. M. Mulder, Genotype impacts survival in Marfan syndrome., Eur. Heart J., 2016, 37, 3285-3290.

A. W. den Hartog, R. Franken, M. P. van den Berg, A. H. Zwinderman, J. Timmermans, A. J. Scholte, V. de Waard, A. M. Spijkerboer, G. Pals, B. J. M. Mulder and M. Groenink, The effect of losartan therapy on ventricular function in Marfan patients with haploinsufficient or dominant negative FBN1 mutations., Neth. Heart J., 2016, 24, 675-681.

D. Micha, E. Voermans, M. E. W. Eekhoff, H. W. van Essen, B. Zandieh-Doulabi, C. Netelenbos, T. Rustemeyer, E. A. Sistermans, G. Pals and N. Bravenboer, Inhibition of TGFbeta signaling decreases osteogenic differentiation of fibrodysplasia ossificans progressiva fibroblasts in a novel in vitro model of the disease., Bone, 2016, 84, 169-180.

R. La Piana, F. K. Cayami, L. T. Tran, K. Guerrero, R. Van Spaendonk, K. ??unap, S. Pajusalu, T. Haack, E. Wassmer, D. Timmann, H. Mierzewska, B. T. Poll-Th??, C. Patel, H. Cox, T. Atik, H. Onay, F. Ozkinay, A. Vanderver, M. S. Van Der Knaap, N. I. Wolf and G. Bernard, Diffuse hypomyelination is not obligate for POLR3-related disorders., Neurology, 2016, 86, 1622-1626.

2015
C. P. B. van der Ploeg, M. E. van den Akker-van Marle, A. M. M. Vernooij-van Langen, L. H. Elvers, J. J. P. Gille, P. H. Verkerk and J. E. Dankert-Roelse, Cost-effectiveness of newborn screening for cystic fibrosis determined with real-life data., J. Cyst. Fibros., 2015, 14, 194-202.

R. Franken, T. Radonic, A. W. den Hartog, M. Groenink, G. Pals, M. van Eijk, R. Lutter, B. J. M. Mulder, A. H. Zwinderman and V. de Waard, The revised role of TGF-beta in aortic aneurysms in Marfan syndrome., Neth. Heart J., 2015, 23, 116-121.

A. W. den Hartog, R. Franken, A. H. Zwinderman, J. Timmermans, A. J. Scholte, M. P. van den Berg, V. de Waard, G. Pals, B. J. M. Mulder and M. Groenink, The risk for type B aortic dissection in Marfan syndrome., J. Am. Coll. Cardiol., 2015, 65, 246-254.

F. K. Cayami, R. La Piana, R. M. L. van Spaendonk, M. Nickel, A. Bley, K. Guerrero, L. T. Tran, M. S. van der Knaap, G. Bernard and N. I. Wolf, POLR3A and POLR3B Mutations in Unclassified Hypomyelination., Neuropediatrics, 2015, 46, 221-228.

R. Jalali, B. Zandieh-Doulabi, P. K. DenBesten, U. Seidler, B. Riederer, S. Wedenoja, D. Micha and A. L. J. J. Bronckers, Slc26a3/Dra and Slc26a6 in Murine Ameloblasts., J. Dent. Res., 2015, 94, 1732-1739.

R. Franken, A. W. den Hartog, T. Radonic, D. Micha, A. Maugeri, F. S. van Dijk, H. E. Meijers-Heijboer, J. Timmermans, A. J. Scholte, M. P. van den Berg, M. Groenink, B. J. M. Mulder, A. H. Zwinderman, V. de Waard and G. Pals, Beneficial Outcome of Losartan Therapy Depends on Type of FBN1 Mutation in Marfan Syndrome., Circ. Cardiovasc. Genet., 2015, 8, 383-388.

D. Micha, D.-C. Guo, Y. Hilhorst-Hofstee, F. van Kooten, D. Atmaja, E. Overwater, F. K. Cayami, E. S. Regalado, R. van Uffelen, H. Venselaar, S. M. H. Faradz, G. Vriend, M. M. Weiss, E. A. Sistermans, A. Maugeri, D. M. Milewicz, G. Pals and F. S. van Dijk, SMAD2 Mutations Are Associated with Arterial Aneurysms and Dissections., Hum. Mutat., 2015, 36, 1145-1149.

N. Bravenboer, D. Micha, J. T. Triffit, A. N. Bullock, R. Ravazollo, R. Bocciardi, M. di Rocco, J. C. Netelenbos, P. Ten Dijke, G. Sanchez-Duffhues, F. S. Kaplan, E. M. Shore, R. J. Pignolo, P. Seemann, F. Ventura, G. Beaujat, E. M. W. Eekhoff and G. Pals, Clinical Utility Gene Card for: Fibrodysplasia ossificans progressiva., Eur. J. Hum. Genet., 2015, 23.

G. R. Monroe, M. Harakalova, S. N. van der Crabben, D. Majoor-Krakauer, A. M. Bertoli-Avella, F. L. Moll, B. I. Oranen, D. Dooijes, A. Vink, N. V Knoers, A. Maugeri, G. Pals, I. J. Nijman, G. van Haaften and A. F. Baas, Familial Ehlers-Danlos syndrome with lethal arterial events caused by a mutation  in COL5A1., Am. J. Med. Genet. A, 2015, 167, 1196-1203.

E. Cancrinus, A. W. J. Hoksbergen, G. J. Pals, W. Wisselink and K. K. Yeung, [Loeys-Dietz syndrome: aortic dissections and aneurysms]., Ned. Tijdschr. Geneeskd., 2015, 159, A8342.

2014
A. Onoufriadis, A. Shoemark, M. M. Munye, C. T. James, M. Schmidts, M. Patel, E. M. Rosser, C. Bacchelli, P. L. Beales, P. J. Scambler, S. L. Hart, J. E. Danke-Roelse, J. J. Sloper, S. Hull, C. Hogg, R. D. Emes, G. Pals, A. T. Moore, E. M. K. Chung and H. M. Mitchison, Combined exome and whole-genome sequencing identifies mutations in ARMC4 as a cause of primary ciliary dyskinesia with defects in the outer dynein arm., J. Med. Genet., 2014, 51, 61-67.

J. J. J. Aalberts, J. P. van Tintelen, L. J. Meijboom, A. Polko, J. D. H. Jongbloed, H. van der Wal, G. Pals, J. Osinga, J. Timmermans, J. de Backer, M. K. Bakker, D. J. van Veldhuisen, R. M. W. Hofstra, B. J. M. Mulder and M. P. van den Berg, Relation between genotype and left-ventricular dilatation in patients with Marfan syndrome., Gene, 2014, 534, 40-43.

B. Nota, J. D. T. Ndika, J. M. van de Kamp, W. A. Kanhai, S. J. M. van Dooren, M. A. van de Wiel, G. Pals and G. S. Salomons, RNA sequencing of creatine transporter (SLC6A8) deficient fibroblasts reveals impairment of the extracellular matrix., Hum. Mutat., 2014, 35, 1128-1135.

T. Paff, J. M. A. Daniels, G. Pals and E. G. Haarman, Primary ciliary dyskinesia: From diagnosis to molecular mechanisms., J. Pediatr. Genet., 2014, 3, 115-127.

2013
M. Harakalova, J. van der Smagt, C. G. F. de Kovel, R. Van't Slot, M. Poot, I. J. Nijman, J. Medic, I. Joziasse, J. Deckers, J. W. Roos-Hesselink, M. W. Wessels, H. F. Baars, M. M. Weiss, G. Pals, L. Golmard, X. Jeunemaitre, D. Lindhout, E. Cuppen and A. F. Baas, Incomplete segregation of MYH11 variants with thoracic aortic aneurysms and dissections and patent ductus arteriosus., Eur. J. Hum. Genet., 2013, 21, 487-493.

F. S. van Dijk, R. Dalgleish, F. Malfait, A. Maugeri, A. Rusinska, O. Semler, S. Symoens and G. Pals, Clinical utility gene card for: osteogenesis imperfecta., Eur. J. Hum. Genet., 2013, 21.

D. J. Moore, A. Onoufriadis, A. Shoemark, M. A. Simpson, P. I. zur Lage, S. C. de Castro, L. Bartoloni, G. Gallone, S. Petridi, W. J. Woollard, D. Antony, M. Schmidts, T. Didonna, P. Makrythanasis, J. Bevillard, N. P. Mongan, J. Djakow, G. Pals, J. S. Lucas, J. K. Marthin, K. G. Nielsen, F. Santoni, M. Guipponi, C. Hogg, S. E. Antonarakis, R. D. Emes, E. M. K. Chung, N. D. E. Greene, J.-L. Blouin, A. P. Jarman and H. M. Mitchison, Mutations in ZMYND10, a gene essential for proper axonemal assembly of inner and  outer dynein arms in humans and flies, cause primary ciliary dyskinesia., Am. J. Hum. Genet., 2013, 93, 346-356.

A. Onoufriadis, T. Paff, D. Antony, A. Shoemark, D. Micha, B. Kuyt, M. Schmidts, S. Petridi, J. E. Dankert-Roelse, E. G. Haarman, J. M. A. Daniels, R. D. Emes, R. Wilson, C. Hogg, P. J. Scambler, E. M. K. Chung, G. Pals and H. M. Mitchison, Splice-site mutations in the axonemal outer dynein arm docking complex gene CCDC114 cause primary ciliary dyskinesia., Am. J. Hum. Genet., 2013, 92, 88-98.

F. S. van Dijk, M. C. Zillikens, D. Micha, M. Riessland, C. L. M. Marcelis, C. E. de Die-Smulders, J. Milbradt, A. A. Franken, A. J. Harsevoort, K. D. Lichtenbelt, H. E. Pruijs, M. E. Rubio-Gozalbo, R. Zwertbroek, Y. Moutaouakil, J. Egthuijsen, M. Hammerschmidt, R. Bijman, C. M. Semeins, A. D. Bakker, V. Everts, J. Klein-Nulend, N. Campos-Obando, A. Hofman, G. J. te Meerman, A. J. M. H. Verkerk, A. G. Uitterlinden, A. Maugeri, E. A. Sistermans, Q. Waisfisz, H. Meijers-Heijboer, B. Wirth, M. E. H. Simon and G. Pals, PLS3 mutations in X-linked osteoporosis with fractures., N. Engl. J. Med., 2013, 369, 1529-1536.

Y. Hilhorst-Hofstee, A. J. H. A. Scholte, M. E. B. Rijlaarsdam, A. van Haeringen, L. J. Kroft, M. Reijnierse, C. A. L. Ruivenkamp, M. I. M. Versteegh, G. Pals and M. H. Breuning, An unanticipated copy number variant of chromosome 15 disrupting SMAD3 reveals a  three-generation family at serious risk for aortic dissection., Clin. Genet., 2013, 83, 337-344.

T. Paff, M. P. van der Schee, J. M. A. Daniels, G. Pals, P. E. Postmus, P. J. Sterk and E. G. Haarman, Exhaled molecular profiles in the assessment of cystic fibrosis and primary ciliary dyskinesia., J. Cyst. Fibros., 2013, 12, 454-460.

U. Schwarze, T. Cundy, S. M. Pyott, H. E. Christiansen, M. R. Hegde, R. A. Bank, G. Pals, A. Ankala, K. Conneely, L. Seaver, S. M. Yandow, E. Raney, D. Babovic-Vuksanovic, J. Stoler, Z. Ben-Neriah, R. Segel, S. Lieberman, L. Siderius, A. Al-Aqeel, M. Hannibal, L. Hudgins, E. McPherson, M. Clemens, M. D. Sussman, R. D. Steiner, J. Mahan, R. Smith, K. Anyane-Yeboa, J. Wynn, K. Chong, T. Uster, S. Aftimos, V. R. Sutton, E. C. Davis, L. S. Kim, M. A. Weis, D. Eyre and P. H. Byers, Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen., Hum. Mol. Genet., 2013, 22, 1-17.

2012
F. S. van Dijk, J. M. Cobben, A. Maugeri, P. G. J. Nikkels, R. R. van Rijn and G. Pals, [Osteogenesis imperfecta: clinical and genetic heterogeneity]., Ned. Tijdschr. Geneeskd., 2012, 156, A4585.

T. Radonic, P. de Witte, M. Groenink, V. de Waard, R. Lutter, M. van Eijk, M. Jansen, J. Timmermans, M. Kempers, A. J. Scholte, Y. Hilhorst-Hofstee, M. P. van den Berg, J. P. van Tintelen, G. Pals, M. J. H. Baars, B. J. M. Mulder and A. H. Zwinderman, Inflammation aggravates disease severity in Marfan syndrome patients., PLoS One, 2012, 7, e32963

E. D. Setijowati, F. S. van Dijk, J. M. Cobben, R. R. van Rijn, E. A. Sistermans, S. M. H. Faradz, S. Kawiyana and G. Pals, A novel homozygous 5 bp deletion in FKBP10 causes clinically Bruck syndrome in an Indonesian patient., Eur. J. Med. Genet., 2012, 55, 17-21.

F. V. Gentile, M. Zuntini, A. Parra, L. Battistelli, M. Pandolfi, G. Pals and L. Sangiorgi, 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., Hum. Mutat., 2012, 33, 1697-1707.

F. S. van Dijk, P. H. Byers, R. Dalgleish, F. Malfait, A. Maugeri, M. Rohrbach, S. Symoens, E. A. Sistermans and G. Pals, EMQN best practice guidelines for the laboratory diagnosis of osteogenesis imperfecta., Eur. J. Hum. Genet., 2012, 20, 11-19.

M. Klaassens, E. Reinstein, Y. Hilhorst-Hofstee, J. J. P. Schrander, F. Malfait, H. Staal, L. C. ten Have, J. Blaauw, H. C. J. Roggeveen, D. Krakow, A. De Paepe, M. A. M. van Steensel, G. Pals, J. M. J. Graham and C. T. R. M. Schrander-Stumpel, Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood., Clin. Genet., 2012, 82, 121-130.

I. M. B. H. van de Laar, D. van der Linde, E. H. G. Oei, P. K. Bos, J. H. Bessems, S. M. Bierma-Zeinstra, B. L. van Meer, G. Pals, R. A. Oldenburg, J. A. Bekkers, A. Moelker, B. M. de Graaf, G. Matyas, I. M. E. Frohn-Mulder, J. Timmermans, Y. Hilhorst-Hofstee, J. M. Cobben, H. T. Bruggenwirth, L. van Laer, B. Loeys, J. De Backer, P. J. Coucke, H. C. Dietz, P. J. Willems, B. A. Oostra, A. De Paepe, J. W. Roos-Hesselink, A. M. Bertoli-Avella and M. W. Wessels, Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome., J. Med. Genet., 2012, 49, 47-57.

A. M. M. Vernooij-van Langen, J. G. Loeber, B. Elvers, R. H. Triepels, J. J. P. Gille, C. P. B. Van der Ploeg, S. Reijntjens, E. Dompeling and J. E. Dankert-Roelse, Novel strategies in newborn screening for cystic fibrosis: a prospective controlled study., Thorax, 2012, 67, 289-295.

2011
F. S. van Dijk, P. G. J. Nikkels, N. S. den Hollander, I. M. Nesbitt, R. R. van Rijn, J. M. Cobben and G. Pals, Lethal/severe osteogenesis imperfecta in a large family: a novel homozygous LEPRE1 mutation and bone histological findings., Pediatr. Dev. Pathol., 2011, 14, 228-234.

Y. Hilhorst-Hofstee, B. C. J. Hamel, J. B. G. M. Verheij, M. E. B. Rijlaarsdam, G. M. S. Mancini, J. M. Cobben, C. Giroth, C. A. L. Ruivenkamp, K. B. M. Hansson, J. Timmermans, H. A. Moll, M. H. Breuning and G. Pals, The clinical spectrum of complete FBN1 allele deletions., Eur. J. Hum. Genet., 2011, 19, 247-252.

F. S. van Dijk, J. M. Cobben, A. Kariminejad, A. Maugeri, P. G. J. Nikkels, R. R. van Rijn and G. Pals, Osteogenesis Imperfecta: A Review with Clinical Examples., Mol. Syndromol., 2011, 2, 1-20.

I. M. B. H. van de Laar, R. A. Oldenburg, G. Pals, J. W. Roos-Hesselink, B. M. de Graaf, J. M. A. Verhagen, Y. M. Hoedemaekers, R. Willemsen, L.-A. Severijnen, H. Venselaar, G. Vriend, P. M. Pattynama, M. Collee, D. Majoor-Krakauer, D. Poldermans, I. M. E. Frohn-Mulder, D. Micha, J. Timmermans, Y. Hilhorst-Hofstee, S. M. Bierma-Zeinstra, P. J. Willems, J. M. Kros, E. H. G. Oei, B. A. Oostra, M. W. Wessels and A. M. Bertoli-Avella, Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis., Nat. Genet., 2011, 43, 121-126.

L. R. E. Harrison, D. Micha, M. Brandenburg, K. L. Simpson, C. J. Morrow, O. Denneny, C. Hodgkinson, Z. Yunus, C. Dempsey, D. Roberts, F. Blackhall, G. Makin and C. Dive, Hypoxic human cancer cells are sensitized to BH-3 mimetic-induced apoptosis via downregulation of the Bcl-2 protein Mcl-1., J. Clin. Invest., 2011, 121, 1075-1087.

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