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  Molecular analysis of two novel missense mutations in the GDF5 proregion that reduce protein activity and are associated with brachydactyly type C

Stange, K., Thieme, T., Hertel, K., Kuhfahl, S., Janecke, A. R., Piza-Katzer, H., et al. (2014). Molecular analysis of two novel missense mutations in the GDF5 proregion that reduce protein activity and are associated with brachydactyly type C. Journal of Molecular Biology, 426(19), 3221-3231. doi:10.1016/j.jmb.2014.07.029.

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© 2014 Elsevier B.V.
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Stange, K., Author
Thieme, T., Author
Hertel, K., Author
Kuhfahl, S., Author
Janecke, A. R., Author
Piza-Katzer, H., Author
Penttinen, M., Author
Hietala, M., Author
Dathe, K., Author
Mundlos, S.1, Author           
Schwarz, E., Author
Seemann, P., Author
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              

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Free keywords: Amino Acid Sequence Bone Development/*genetics Bone Morphogenetic Protein Receptors, Type I/metabolism Bone and Bones/embryology Brachydactyly/*genetics Cartilage/embryology/growth & development Cell Differentiation/genetics Cell Proliferation/genetics Chondrogenesis/*genetics Growth Differentiation Factor 5/*genetics Heterozygote Humans Karyotype Mutation, Missense Sequence Alignment Smad Proteins/metabolism
 Abstract: Growth and differentiation factor 5 (GDF5) plays a central role in bone and cartilage development by regulating the proliferation and differentiation of chondrogenic tissue. GDF5 is synthesized as a preproprotein. The biological function of the proregion comprising 354 residues is undefined. We identified two families with a heterozygosity for the novel missense mutations p.T201P or p.L263P located in the proregion of GDF5. The patients presented with dominant brachydactyly type C characterized by the shortening of skeletal elements in the distal extremities. Both mutations gave rise to decreased biological activity in in vitro analyses. The variants reduced the GDF5-induced activation of SMAD signaling by the GDF5 receptors BMPR1A and BMPR1B. Ectopic expression in micromass cultures yielded relatively low protein levels of the variants and showed diminished chondrogenic activity as compared to wild-type GDF5. Interestingly, stimulation of micromass cells with recombinant human proGDF5(T201P) and proGDF5(L263P) revealed their reduced chondrogenic potential compared to the wild-type protein. Limited proteolysis of the mutant recombinant proproteins resulted in a fragment pattern profoundly different from wild-type proGDF5. Modeling of a part of the GDF5 proregion into the known three-dimensional structure of TGFbeta1 latency-associated peptide revealed that the homologous positions of both mutations are conserved regions that may be important for the folding of the mature protein or the assembly of dimeric protein complexes. We hypothesize that the missense mutations p.T201P and p.L263P interfere with the protein structure and thereby reduce the amount of fully processed, biologically active GDF5, finally causing the clinical loss of function phenotype.

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Language(s): eng - English
 Dates: 2014-08-012014-09-23
 Publication Status: Issued
 Pages: -
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1016/j.jmb.2014.07.029
ISSN: 1089-8638 (Electronic)0022-2836 (Print)
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Title: Journal of Molecular Biology
Source Genre: Journal
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Publ. Info: Elsevier
Pages: - Volume / Issue: 426 (19) Sequence Number: - Start / End Page: 3221 - 3231 Identifier: -