A GDF5 Point Mutation Strikes Twice - Causing BDA1 and SYNS2

English version České info

Growth and Differentiation Factor 5 (GDF5) is a secreted growth factor that belongs to the Bone Morphogenetic Protein (BMP) family and plays a pivotal role during limb development. GDF5 is a susceptibility gene for osteoarthritis (OA) and mutations in GDF5 are associated with a wide variety of skeletal malformations ranging from complex syndromes such as acromesomelic chondrodysplasias to isolated forms of brachydactylies or multiple synostoses syndrome 2 (SYNS2). Here, we report on a family with an autosomal dominant inherited combination of SYNS2 and additional brachydactyly type A1 (BDA1) caused by a single point mutation in GDF5 (p.W414R). Functional studies, including chondrogenesis assays with primary mesenchymal cells, luciferase reporter gene assays and Surface Plasmon Resonance analysis, of the GDF5^W414R variant in comparison to other GDF5 mutations associated with isolated BDA1 (p.R399C) or SYNS2 (p.E491K) revealed a dual pathomechanism characterized by a gain- and loss-of-function at the same time. On the one hand insensitivity to the main GDF5 antagonist NOGGIN (NOG) leads to a GDF5 gain of function and subsequent SYNS2 phenotype. Whereas on the other hand, a reduced signaling activity, specifically via the BMP receptor type IA (BMPR1A), is likely responsible for the BDA1 phenotype. These results demonstrate that one mutation in the overlapping interface of antagonist and receptor binding site in GDF5 can lead to a GDF5 variant with pathophysiological relevance for both, BDA1 and SYNS2 development. Consequently, our study assembles another part of the molecular puzzle of how loss and gain of function mutations in GDF5 affect bone development in hands and feet resulting in specific types of brachydactyly and SYNS2. These novel insights into the biology of GDF5 might also provide further clues on the pathophysiology of OA.

Vyšlo v časopise: A GDF5 Point Mutation Strikes Twice - Causing BDA1 and SYNS2. PLoS Genet 9(10): e32767. doi:10.1371/journal.pgen.1003846
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003846

Souhrn

Zdroje

1. ChangSC, HoangB, ThomasJT, VukicevicS, LuytenFP, et al. (1994) Cartilage-derived morphogenetic proteins. New members of the transforming growth factor-beta superfamily predominantly expressed in long bones during human embryonic development. J Biol Chem 269: 28227–28234.

2. StrickerS, MundlosS (2011) Mechanisms of Digit Formation: Human Malformation Syndromes Tell the Story. Developmental Dynamics 240: 990–1004.

3. BuxtonP, EdwardsC, ArcherCW, Francis-WestP (2001) Growth/differentiation factor-5 (GDF-5) and skeletal development. J Bone Joint Surg Am 83-A Suppl 1: S23–30.

4. StormEE, HuynhTV, CopelandNG, JenkinsNA, KingsleyDM, et al. (1994) Limb alterations in brachypodism mice due to mutations in a new member of the TGF beta-superfamily. Nature 368: 639–643.

5. KotzschA, NickelJ, SeherA, SebaldW, MullerTD (2009) Crystal structure analysis reveals a spring-loaded latch as molecular mechanism for GDF-5-type I receptor specificity. EMBO J 28: 937–947.

6. MuellerTD, NickelJ (2012) Promiscuity and specificity in BMP receptor activation. FEBS Lett 586: 1846–1859.

7. NoheA, KeatingE, KnausP, PetersenNO (2004) Signal transduction of bone morphogenetic protein receptors. Cell Signal 16: 291–299.

8. SchmiererB, HillCS (2007) TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol 8: 970–982.

9. MiyazonoK, KamiyaY, MorikawaM (2010) Bone morphogenetic protein receptors and signal transduction. J Biochem 147: 35–51.

10. BragdonB, MoseychukO, SaldanhaS, KingD, JulianJ, et al. (2011) Bone morphogenetic proteins: a critical review. Cell Signal 23: 609–620.

11. MundlosS (2009) The brachydactylies: a molecular disease family. Clin Genet 76: 123–136.

12. LoriesRJ, LuytenFP (2005) Bone morphogenetic protein signaling in joint homeostasis and disease. Cytokine Growth Factor Rev 16: 287–298.

13. DawsonK, SeemanP, SebaldE, KingL, EdwardsM, et al. (2006) GDF5 is a second locus for multiple-synostosis syndrome. Am J Hum Genet 78: 708–712.

14. WangX, XiaoF, YangQ, LiangB, TangZ, et al. (2006) A novel mutation in GDF5 causes autosomal dominant symphalangism in two Chinese families. Am J Med Genet A 140A: 1846–1853.

15. SeemannP, BrehmA, KonigJ, ReissnerC, StrickerS, et al. (2009) Mutations in GDF5 reveal a key residue mediating BMP inhibition by NOGGIN. PLoS Genet 5: e1000747.

16. SeemannP, SchwappacherR, KjaerKW, KrakowD, LehmannK, et al. (2005) Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2. J Clin Invest 115: 2373–2381.

17. SchwaerzerGK, HiepenC, SchreweH, NickelJ, PloegerF, et al. (2012) New insights into the molecular mechanism of multiple synostoses syndrome (SYNS): mutation within the GDF5 knuckle epitope causes noggin-resistance. J Bone Miner Res 27: 429–442.

18. PlogerF, SeemannP, Schmidt-von KeglerM, LehmannK, SeidelJ, et al. (2008) Brachydactyly type A2 associated with a defect in proGDF5 processing. Hum Mol Genet 17: 1222–1233.

19. ByrnesAM, RacachoL, NikkelSM, XiaoF, MacDonaldH, et al. (2010) Mutations in GDF5 presenting as semidominant brachydactyly A1. Hum Mutat 31: 1155–1162.

20. SchwabeGC, TurkmenS, LeschikG, PalanduzS, StoverB, et al. (2004) Brachydactyly type C caused by a homozygous missense mutation in the prodomain of CDMP1. Am J Med Genet A 124A: 356–363.

21. EvermanDB, BartelsCF, YangY, YanamandraN, GoodmanFR, et al. (2002) The mutational spectrum of brachydactyly type C. Am J Med Genet 112: 291–296.

22. ThomasJT, KilpatrickMW, LinK, ErlacherL, LembessisP, et al. (1997) Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1. Nat Genet 17: 58–64.

23. NickelJ, KotzschA, SebaldW, MuellerTD (2005) A single residue of GDF-5 defines binding specificity to BMP receptor IB. J Mol Biol 349: 933–947.

24. KellerS, NickelJ, ZhangJL, SebaldW, MuellerTD (2004) Molecular recognition of BMP-2 and BMP receptor IA. Nat Struct Mol Biol 11: 481–488.

25. KirschT, SebaldW, DreyerMK (2000) Crystal structure of the BMP-2-BRIA ectodomain complex. Nat Struct Biol 7: 492–496.

26. GroppeJ, GreenwaldJ, WiaterE, Rodriguez-LeonJ, EconomidesAN, et al. (2002) Structural basis of BMP signalling inhibition by the cystine knot protein Noggin. Nature 420: 636–642.

27. GongY, KrakowD, MarcelinoJ, WilkinD, ChitayatD, et al. (1999) Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis. Nat Genet 21: 302–304.

28. BrownDJ, KimTB, PettyEM, DownsCA, MartinDM, et al. (2002) Autosomal dominant stapes ankylosis with broad thumbs and toes, hyperopia, and skeletal anomalies is caused by heterozygous nonsense and frameshift mutations in NOG, the gene encoding noggin. Am J Hum Genet 71: 618–624.

29. ManginoM, FlexE, DigilioMC, GiannottiA, DallapiccolaB (2002) Identification of a novel NOG gene mutation (P35S) in an Italian family with symphalangism. Hum Mutat 19: 308.

30. LehmannK, SeemannP, SilanF, GoeckeTO, IrgangS, et al. (2007) A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN. Am J Hum Genet 81: 388–396.

31. YoonBS, OvchinnikovDA, YoshiiI, MishinaY, BehringerRR, et al. (2005) Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo. Proc Natl Acad Sci U S A 102: 5062–5067.

32. ZouH, WieserR, MassagueJ, NiswanderL (1997) Distinct roles of type I bone morphogenetic protein receptors in the formation and differentiation of cartilage. Genes Dev 11: 2191–2203.

33. VortkampA, LeeK, LanskeB, SegreGV, KronenbergHM, et al. (1996) Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science 273: 613–622.

34. MininaE, WenzelHM, KreschelC, KarpS, GaffieldW, et al. (2001) BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation and differentiation. Development 128: 4523–4534.

35. LehmannK, SeemannP, StrickerS, SammarM, MeyerB, et al. (2003) Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2. Proc Natl Acad Sci U S A 100: 12277–12282.

36. ReynardLN, LoughlinJ (2012) Genetics and epigenetics of osteoarthritis. Maturitas 71: 200–204.

37. LiuJ, CaiW, ZhangH, HeC, DengL (2013) Rs143383 in the Growth Differentiation Factor 5 (GDF5) Gene Significantly Associated with Osteoarthritis (OA)-A Comprehensive Meta-analysis. Int J Med Sci 10: 312–319.

38. DaansM, LuytenFP, LoriesRJ (2011) GDF5 deficiency in mice is associated with instability-driven joint damage, gait and subchondral bone changes. Ann Rheum Dis 70: 208–213.

39. MasuyaH, NishidaK, FuruichiT, TokiH, NishimuraG, et al. (2007) A novel dominant-negative mutation in Gdf5 generated by ENU mutagenesis impairs joint formation and causes osteoarthritis in mice. Hum Mol Genet 16: 2366–2375.

40. MorganBA, FeketeDM (1996) Manipulating gene expression with replication-competent retroviruses. Methods Cell Biol 51: 185–218.

41. JonkLJ, ItohS, HeldinCH, ten DijkeP, KruijerW (1998) Identification and functional characterization of a Smad binding element (SBE) in the JunB promoter that acts as a transforming growth factor-beta, activin, and bone morphogenetic protein-inducible enhancer. J Biol Chem 273: 21145–21152.

42. HampfM, GossenM (2006) A protocol for combined Photinus and Renilla luciferase quantification compatible with protein assays. Anal Biochem 356: 94–99.

43. YiSE, DaluiskiA, PedersonR, RosenV, LyonsKM (2000) The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb. Development 127: 621–630.

44. PryceBA, BrentAE, MurchisonND, TabinCJ, SchweitzerR (2007) Generation of transgenic tendon reporters, ScxGFP and ScxAP, using regulatory elements of the scleraxis gene. Dev Dyn 236: 1677–1682.

45. SharpeJ, AhlgrenU, PerryP, HillB, RossA, et al. (2002) Optical projection tomography as a tool for 3D microscopy and gene expression studies. Science 296: 541–545.

46. QuintanaL, SharpeJ (2011) Preparation of mouse embryos for optical projection tomography imaging. Cold Spring Harb Protoc 2011: 664–669.

47. RobinsonPN, KohlerS, BauerS, SeelowD, HornD, et al. (2008) The Human Phenotype Ontology: a tool for annotating and analyzing human hereditary disease. Am J Hum Genet 83: 610–615.