Mutations in GDF5 Reveal a Key Residue Mediating BMP Inhibition by NOGGIN

被引:80
|
作者
Seemann, Petra [1 ,2 ]
Brehm, Anja [1 ,2 ,3 ,4 ]
Koenig, Jana [1 ,2 ,4 ]
Reissner, Carsten [5 ]
Stricker, Sigmar [1 ]
Kuss, Pia [1 ,3 ,4 ]
Haupt, Julia [1 ,2 ,3 ,4 ]
Renninger, Stephanie [1 ,3 ]
Nickel, Joachim [6 ]
Sebald, Walter [6 ]
Groppe, Jay C. [7 ]
Ploeger, Frank [8 ]
Pohl, Jens [8 ]
Schmidt-von Kegler, Mareen [1 ,3 ]
Walther, Maria [1 ]
Gassner, Ingmar [9 ]
Rusu, Cristina [10 ]
Janecke, Andreas R. [11 ]
Dathe, Katarina [3 ]
Mundlos, Stefan [1 ,2 ,3 ]
机构
[1] Max Planck Inst Mol Genet, Res Grp Dev & Dis, Berlin, Germany
[2] Charite, Berlin Brandenburg Ctr Regenerat Therapies, D-13353 Berlin, Germany
[3] Charite, Inst Med Genet, D-13353 Berlin, Germany
[4] Free Univ Berlin, D-1000 Berlin, Germany
[5] Univ Klinikum Munster, Dept Anat & Mol Neurobiol, Inst Anat, Munster, Germany
[6] Univ Wurzburg, Biozentrum, Theodor Boveri Inst Biowissensch, Lehrstuhl Physiol Chem 2, Wurzburg, Germany
[7] Texas A&M Univ Syst, Hlth Sci Ctr, Baylor Coll Dent, Dept Biomed Sci, Dallas, TX USA
[8] Biopharm GmbH, Heidelberg, Germany
[9] Med Univ Innsbruck, Dept Kinder & Jugendheilkunde, Innsbruck, Austria
[10] Univ Med & Pharm, Dept Med Genet, Iasi, Romania
[11] Med Univ Innsbruck, Sekt Klin Genet, Innsbruck, Austria
关键词
BRACHYDACTYLY TYPE-C; CRYSTAL-STRUCTURE; SPEMANN ORGANIZER; POINT MUTATIONS; BONE; EXPRESSION; GROWTH; GENE; DIFFERENTIATION; IDENTIFICATION;
D O I
10.1371/journal.pgen.1000747
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Signaling output of bone morphogenetic proteins (BMPs) is determined by two sets of opposing interactions, one with heterotetrameric complexes of cell surface receptors, the other with secreted antagonists that act as ligand traps. We identified two mutations (N445K, T) in patients with multiple synostosis syndrome (SYM1) in the BMP-related ligand GDF5. Functional studies of both mutants in chicken micromass culture demonstrated a gain of function caused by a resistance to the BMP-inhibitor NOGGIN and an altered signaling effect. Residue N445, situated within overlapping receptor and antagonist interfaces, is highly conserved among the BMP family with the exception of BMP9 and BMP10, in which it is substituted with lysine. Like the mutant GDF5, both BMPs are insensitive to NOGGIN and show a high chondrogenic activity. Ectopic expression of BMP9 or the GDF5 mutants resulted in massive induction of cartilage in an in vivo chick model presumably by bypassing the feedback inhibition imposed by endogenous NOGGIN. Swapping residues at the mutation site alone was not sufficient to render Bmp9 NOG-sensitive; however, successive introduction of two additional substitutions imparted high to total sensitivity on customized variants of Bmp9. In conclusion, we show a new mechanism for abnormal joint development that interferes with a naturally occurring regulatory mechanism of BMP signaling.
引用
收藏
页数:11
相关论文
共 41 条
  • [1] Formation and characterization of BMP2/GDF5 and BMP4/GDF5 heterodimers
    Gregory R. Gipson
    Kristof Nolan
    Chandramohan Kattamuri
    Alan P. Kenny
    Zachary Agricola
    Nicole A. Edwards
    Joseph Zinski
    Magdalena Czepnik
    Mary C. Mullins
    Aaron M. Zorn
    Thomas B. Thompson
    [J]. BMC Biology, 21
  • [2] Formation and characterization of BMP2/GDF5 and BMP4/GDF5 heterodimers
    Gipson, Gregory R.
    Nolan, Kristof
    Kattamuri, Chandramohan
    Kenny, Alan P.
    Agricola, Zachary
    Edwards, Nicole A.
    Zinski, Joseph
    Czepnik, Magdalena
    Mullins, Mary C.
    Zorn, Aaron M.
    Thompson, Thomas B.
    [J]. BMC BIOLOGY, 2023, 21 (01)
  • [3] GDF5 mutations:: from phenotypes to function
    Seemann, P
    Schwappacher, R
    Krakow, D
    Lehmann, K
    Dawson, K
    Stricker, S
    Pohl, J
    Plöger, F
    Staub, E
    Nickel, J
    Sebald, W
    Knaus, P
    Mundlos, S
    [J]. INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, 2006, 87 (01) : A29 - A30
  • [4] Identification of a Key Residue Mediating Bone Morphogenetic Protein (BMP)-6 Resistance to Noggin Inhibition Allows for Engineered BMPs with Superior Agonist Activity
    Song, Kening
    Krause, Carola
    Shi, Songting
    Patterson, Marilyn
    Suto, Robert
    Grgurevic, Lovorka
    Vukicevic, Slobodan
    van Dinther, Maarten
    Falb, Dean
    ten Dijke, Peter
    Alaoui-Ismaili, Moulay Hicham
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285 (16) : 12169 - 12180
  • [5] BMP2 and GDF5 for Compartmentalized Regeneration of the Scapholunate Ligament
    Lui, Hayman
    Vaquette, Cedryck
    Denbeigh, Janet M.
    Bindra, Randy
    van Wijnen, Andre J.
    Kakar, Sanjeev
    [J]. JOURNAL OF WRIST SURGERY, 2023, 12 (05) : 418 - 427
  • [6] Distinct functions of BMP4 and GDF5 in the regulation of chondrogenesis
    Hatakeyama, Y
    Tuan, RS
    Shum, L
    [J]. JOURNAL OF CELLULAR BIOCHEMISTRY, 2004, 91 (06) : 1204 - 1217
  • [7] Mutations in GDF5 Presenting as Semidominant Brachydactyly A1
    Byrnes, Ashley M.
    Racacho, Lemuel
    Nikkel, Sarah M.
    Xiao, Fengxia
    MacDonald, Heather
    Underhill, T. Michael
    Bulman, Dennis E.
    [J]. HUMAN MUTATION, 2010, 31 (10) : 1155 - 1162
  • [8] 脂肪间充质干细胞中Noggin下调能够促进GDF5的表达
    刘浩
    陆征峰
    杨凯
    张圣智
    汤峰林
    陆淼
    丁涛
    [J]. 南京医科大学学报(自然科学版), 2018, 38 (09) : 1181 - 1186
  • [9] GDF5 is associated with a variety of skeletal malformations due to gain or loss of function mutations
    Degenkolbe, E.
    Koenig, J.
    Zimmer, J.
    Walther, M.
    Dathe, K.
    Mundlos, S.
    Doelken, S. C.
    Seemann, P.
    [J]. BONE, 2012, 51 (06) : S10 - S10
  • [10] Two Novel Homozygous Missense Mutations in the GDF5 Gene Cause Brachydactyly Type C
    Al-Qattan, Mohammad M.
    Al-Motairi, Muhammed I.
    Al Balwi, Mohammed A.
    [J]. AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 2015, 167 (07) : 1621 - 1626