Molecular mechanisms of congenital limb malformations [Elektronische Ressource] / Barbara Pawlik

Pawlik_B

Sujets

• Biologie

Informations

• Publié par: universitat_zu_koln
• Publié le: 01 janvier 2010
• Nombre de lectures: 76
• Langue: English
• Poids de l'ouvrage: 4 Mo

Extrait

Molecular mechanisms of congenital limb malformations


Inaugural Dissertation


zur
Erlangung des Doktorgrades
Dr. nat. med.
der Medizinischen Fakultät
und
der Mathematisch-Naturwissenschaftlichen Fakultät
der Universität zu Köln

vorgelegt von
Dipl. Biol. Barbara Pawlik
aus Ratibor (Polen)


Köln, 2010

Gutachter: Prof. Dr. Gabriele Pfitzer
Prof. Dr. Peter Nürnberg

Tag der letzten mündlichen Prüfung: 18.10.2010


























Contents
1. List of Publications............................................................................................ 1
1.1 Main publications on human limb malformations ........................................................... 1
1.2 Publications derived from additional projects.................................................................. 2
2. Abstract.............................................................................................................. 3
2. Zusammenfassung............................................................................................. 4
3. Introduction ....................................................................................................... 6
3.1 Vertebrate limb development ........................................................................................... 6
3.2 Signalling pathways important in limb development....................................................... 8
3.2.1 The Shh signalling pathway ...................................................................................... 8
3.2.2 Fgf signalling............................................................................................................. 9
3.2.3 The canonical Wnt signalling pathway ................................................................... 10
3.2.3.1 Wnt signalling in limb development .............................................................. 12
3.2.3.2 Low-density lipoprotein receptor-related proteins 4 and 6 (Lrp4 & Lrp6).... 12
3. 3 Human limb malformation syndromes.......................................................................... 15
3.3.1 Phenotypes investigated in this study...................................................................... 17
3.3.1.1 Cenani-Lenz syndrome................................................................................... 17
3.3.1.2 Werner mesomelic syndrome......................................................................... 18
3.3.1.3 Split-hand/foot malformation......................................................................... 18
3.3.1.4 Bardet-Biedl syndrome .................................................................................. 18
3.3.2 Molecular pathogenesis of SHH limb phenotypes.................................................. 19
3.3.3 Limb phenotypes due to defective Wnt signalling.................................................. 20
3.3.4 Molecular pathogenesis of split-hand/foot malformation (SHFM) phenotypes ..... 21
3.3.5 Molecular pathogenesis of Bardet-Biedl (BBS) syndrome..................................... 22
4. Aims and major findings of this Ph.D thesis...................................................22
4.1 Aims ............................................................................................................................... 22
4.2 Major findings ................................................................................................................ 23
5. Main publications on human limb malformations with own contributions....24
5.1 A Novel Familial BBS12 Mutation Associated with a Mild Phenotype: Implications for
Clinical and Molecular Diagnostic Strategies. (Pawlik et al., 2010) Mol Syndromol (2010);
1:27-34. ................................................................................................................................ 24
5.2 LRP4 Mutations Alter Wnt/b-Catenin Signalling and Cause Limb and Kidney
Malformations in Cenani-Lenz Syndrome. (Li et al., 2010) Am J Hum Genet (2010);
86(5):696-706....................................................................................................................... 26
5.3 A specific mutation in the distant sonic hedgehog cis-regulator (ZRS) causes Werner
mesomelic syndrome while complete ZRS duplications underlie Haas type polysyndactyly
and preaxial polydactyly with or without triphalangeal thumb. (Wieczorek et al., 2010)
Hum Mutat. (2010); 31(1):81-9. .......................................................................................... 29
5.4 Reduced LRP6-mediated WNT10B signalling in the pathogenesis of SHFM6. (Pawlik
et al., submitted) ................................................................................................................... 31
5.5 Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in
Chondroitin synthase 1, a potential target of BMP signalling (Li et al., 2010) in Press Am J
Hum Genet (2010)................................................................................................................ 34
6. Publications derived from additional projects during this Ph.d......................37
6.1 A novel loss-of-function mutation in the GNS gene causes Sanfilippo syndrome type D.
(Elçioglu et al., 2009) Genet Couns (2009); 20(2):133-9. .................................................. 37
6.2 Mutation analysis of TMC1 identifies four new mutations and suggests an additional
deafness gene at loci DFNA36 and DFNB7/11. (Hilgert et al., 2008) Clin Genet. (2008);
74(3):223-32......................................................................................................................... 39
7. Conclusions .....................................................................................................41
8. References .......................................................................................................42
9. Appendix: Acknowledgements and Academic Curriculum Vitae..................48


1. List of Publications
This Ph.D thesis is based on the following publications:
1.1 Main publications on human limb malformations
Pawlik B, Mir A, Iqbal H, Li Y, Nürnberg G, Becker C, Qamar R, Nürnberg P, Wollnik B. A
Novel Familial BBS12 Mutation Associated with a Mild Phenotype: Implications for
Clinical and Molecular Diagnostic Strategies. Mol Syndromol (2010); 1:27-34.

Li Y*, Pawlik B*, Elcioglu N, Aglan M, Kayserili H, Yigit G, Percin F, Goodman F,
Nürnberg G, Cenani A, Urquhart J, Chung B, Ismail S, Amr K, Aslanger AD, Becker C,
Netzer C, Scambler P, Eyaid W, Hamamy H, Clayton-Smith Y, Hennekam R, Nürnberg P,
Herz J, Temtamy SA, Wollnik B. LRP4 Mutations Alter Wnt/b-Catenin Signalling and
Cause Limb and Kidney Malformations in Cenani-Lenz Syndrome. Am J Hum Genet
(2010); 86(5):696-706.
* These authors contributed equally to this work

Wieczorek D, Pawlik B, Li Y, Akarsu NA, Caliebe A, May KJ, Schweiger B, Vargas FR,
Balci S, Gillessen-Kaesbach G, Wollnik B. A specific mutation in the distant sonic
hedgehog cis-regulator (ZRS) causes Werner mesomelic syndrome while complete ZRS
duplications underlie Haas type polysyndactyly and preaxial polydactyly with or
without triphalangeal thumb. Hum Mutat. (2010); 31(1):81-9.

Pawlik B, Yigit G, Wollnik B. Reduced LRP6-mediated WNT10B signalling in the
pathogenesis of SHFM6. (submitted)

Li Y, Laue K, Temtamy S, Aglan M, Kotan L.D, Yigit G, Husniye C, Pawlik B, Nürnberg G,
Wakeling EL, Quarrell OW, Baessmann I, Lanktree MB, Yilmaz M, Hegele RA, Amr K, May
KW, Nürnberg P, Topaloglu AK, Hammerschmidt M, Wollnik B. Temtamy preaxial
brachydactyly syndrome is caused by loss-of-function mutations in Chondroitin
synthase 1, a potential target of BMP signalling. In Press, Am J Hum Genet (2010).



1
1.2 Publications derived from additional projects
Elçioglu NH, Pawlik B, Colak B, Beck M, Wollnik B. A novel loss-of-function mutation in
the GNS gene causes Sanfilippo syndrome type D. Genet Couns (2009); 20(2):133-9.

Hilgert N, Alasti F, Dieltjens N, Pawlik B, Wollnik B, Uyguner O, Delmaghani S, Weil D,
Petit C, Danis E, Yang T, Pandelia E, Petersen MB, Goossens D, Favero JD, Sanati MH,
Smith RJ, Van Camp G. Mutation analysis of TMC1 identifies four new mutations and
suggests an additional deafness gene at loci DFNA36 and DFNB7/11. Clin Genet. (2008);
74(3):223-32.























2
2. Abstract
Congenital limb malformations occur in 1 in 500 to 1 in 1000 human live births and are
diverse in their epidemiology, aetiology and anatomy. The molecular analysis of disturbed
gene function in inherited limb malformations provides essential information for the
understanding of physiological and pathophysiological limb development in humans as well
as in other vertebrates. The following Ph.D thesis focussed on the identification and molecular
c