Attenuated BMP1 Function Compromises Osteogenesis, Leading to Bone Fragility in Humans and Zebrafish

• Published in: American journal of human genetics Vol. 90; no. 4; pp. 661 - 674
• Main Authors: Asharani, P.V., Keupp, Katharina, Semler, Oliver, Wang, Wenshen, Li, Yun, Thiele, Holger, Yigit, Gökhan, Pohl, Esther, Becker, Jutta, Frommolt, Peter, Sonntag, Carmen, Altmüller, Janine, Zimmermann, Katharina, Greenspan, Daniel S., Akarsu, Nurten A., Netzer, Christian, Schönau, Eckhard, Wirth, Radu, Hammerschmidt, Matthias, Nürnberg, Peter, Wollnik, Bernd, Carney, Thomas J.
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 06.04.2012; Cell Press; Elsevier
• Subjects: Animals; Base Sequence; Biological and medical sciences; Bone and Bones - metabolism; Bone Density Conservation Agents - therapeutic use; Bone Morphogenetic Protein 1 - genetics; Bone Morphogenetic Protein 1 - metabolism; Bone Morphogenetic Protein 1 - physiology; Bone Morphogenetic Protein 1 - secretion; Cell Differentiation; Child, Preschool; Collagen - biosynthesis; Danio rerio; Diphosphonates - therapeutic use; Exome; Female; Fractures, Bone - drug therapy; Fractures, Bone - prevention & control; Freshwater; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genetic Loci; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Heat-Shock Proteins; Human subjects; Humans; Male; Medical genetics; Medical sciences; Molecular and cellular biology; Molecular Sequence Data; Mutation; Osteoblasts - drug effects; Osteoblasts - physiology; Osteogenesis - drug effects; Osteogenesis - genetics; Osteogenesis - physiology; Peptide Fragments; Protein Processing, Post-Translational; Proteins; Signal transduction; Zebrafish; Zebrafish - genetics; Zebrafish - metabolism; Human; Vertebrata; Brachydanio rerio; Pisces; Genetics; Bone; Osteogenesis
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2012.02.026

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.