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

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• 作者：P.V. Asharani¹ ; ¹⁰ ; Katharina Keupp² ; ³ ; ⁴ ; ¹⁰ ; Oliver Semler⁵ ; Wenshen Wang¹ ; Yun Li² ; ³ ; ⁴ ; Holger Thiele⁶ ; Gö ; khan Yigit² ; ³ ; ⁴ ; Esther Pohl² ; ³ ; ⁴ ; Jutta Becker³ ; Peter Frommolt⁴ ; ⁶ ; Carmen Sonntag⁷ ; ¹² ; Janine Altmü ; ller⁶ ; Katharina Zimmermann³ ; Daniel  ; S. Greenspan⁸ ; Nurten  ; A. Akarsu⁹ ; Christian Netzer³ ; Eckhard Schö ; nau⁵ ; Radu Wirth³ ; Matthias Hammerschmidt² ; ⁴ ; ⁷ ; Peter Nü ; rnberg² ; ⁴ ; ⁶ ; Bernd Wollnik² ; ³ ; ⁴ ; ¹¹ ; ^{bwollnik@uni-koeln.de} ; Thomas  ; J. Carney¹ ; ¹¹ ; ^{tcarney@imcb.a-star.edu.sg}
• 刊名：The American Journal of Human Genetics
• 出版年：2012
• 出版时间：6 April, 2012
• 年：2012
• 卷：90
• 期：4
• 页码：661-674
• 全文大小：1979 K

文摘

Bone morphogenetic protein 1 (BMP1) is an astacin metalloprotease with important cellular functions and diverse substrates, including extracellular-matrix proteins and antagonists of some TGF¦Â 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.