Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish

P V Asharani, Katharina Keupp, Oliver Semler, Wenshen Wang, Yun Li, Holger Thiele, Gokhan Yigit, Esther Pohl, Jutta Becker, Peter Frommolt, Carmen Sonntag, Janine Altmuller, Katharina Zimmermann, Daniel S Greenspan, Nurten A Akarsu, Christian Netzer, Eckhard Shonau, Radu Wirth, Matthias Hammerschmidt, Peter NurnbergBernd Wollnik, Thomas J Carney

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133 Citations (Scopus)


Bone morphogenetic protein 1 (BMP1) is an astacin metalloprotease with important cellular functions and diverse substrates, including extracellular-matrix proteins and antagonists of some TGFbeta 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.
Original languageEnglish
Pages (from-to)661 - 674
Number of pages14
JournalAmerican Journal of Human Genetics
Issue number4
Publication statusPublished - 2012

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