title: Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish.
abstract: Bone morphogenetic protein 1 (BMP1) is an astacin metalloprotease with important cellular functions and diverse substrates, including extracellular-matrix proteins and antagonists of some TGFβ superfamily members. Combining whole-exome sequencing and filtering for homozygous stretches of identified variants, we found a homozygous causative BMP1 mutation, c.34G>C, in a consanguineous family affected by increased bone mineral density and multiple recurrent fractures. The mutation is located within the BMP1 signal peptide and leads to impaired secretion and an alteration in posttranslational modification. We also characterize a zebrafish bone mutant harboring lesions in bmp1a, demonstrating conservation of BMP1 function in osteogenesis across species. Genetic, biochemical, and histological analyses of this mutant and a comparison to a second, similar locus reveal that Bmp1a is critically required for mature-collagen generation, downstream of osteoblast maturation, in bone. We thus define the molecular and cellular bases of BMP1-dependent osteogenesis and show the importance of this protein for bone formation and stability.
authors.affiliation: Institute of Molecular and Cell Biology, Proteos, Singapore, Singapore.
authors.forename: P V
authors.initials: PV
authors.lastname: Asharani
authors.forename: Katharina
authors.initials: K
authors.lastname: Keupp
authors.forename: Oliver
authors.initials: O
authors.lastname: Semler
authors.forename: Wenshen
authors.initials: W
authors.lastname: Wang
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.forename: Gökhan
authors.initials: G
authors.lastname: Yigit
authors.forename: Esther
authors.initials: E
authors.lastname: Pohl
authors.forename: Jutta
authors.initials: J
authors.lastname: Becker
authors.forename: Peter
authors.initials: P
authors.lastname: Frommolt
authors.forename: Carmen
authors.initials: C
authors.lastname: Sonntag
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.forename: Katharina
authors.initials: K
authors.lastname: Zimmermann
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Greenspan
authors.forename: Nurten A
authors.initials: NA
authors.lastname: Akarsu
authors.forename: Christian
authors.initials: C
authors.lastname: Netzer
authors.forename: Eckhard
authors.initials: E
authors.lastname: Schönau
authors.forename: Radu
authors.initials: R
authors.lastname: Wirth
authors.forename: Matthias
authors.initials: M
authors.lastname: Hammerschmidt
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Carney
mesh_terms: D000818:Animals; D001483:Base Sequence; D050071:Bone Density Conservation Agents / Q000627:therapeutic use; D055395:Bone Morphogenetic Protein 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D001842:Bone and Bones / Q000378:metabolism; D002454:Cell Differentiation; D002675:Child, Preschool; D003094:Collagen / Q000096:biosynthesis; D004164:Diphosphonates / Q000627:therapeutic use; D059472:Exome; D005260:Female; D050723:Fractures, Bone / Q000188:drug therapy / Q000517:prevention & control; D056426:Genetic Loci; D006360:Heat-Shock Proteins; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010006:Osteoblasts / Q000187:drug effects / Q000502:physiology; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D010446:Peptide Fragments; D011499:Protein Processing, Post-Translational; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D006360:Heat-Shock Proteins; D010446:Peptide Fragments; C063820:SNP nonapeptide; D003094:Collagen; C525705:BMP1 protein, human; D055395:Bone Morphogenetic Protein 1