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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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 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
Volume90
Issue number4
DOIs
Publication statusPublished - 2012

Cite this

Asharani, P. V., Keupp, K., Semler, O., Wang, W., Li, Y., Thiele, H., ... Carney, T. J. (2012). Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish. American Journal of Human Genetics, 90(4), 661 - 674. https://doi.org/10.1016/j.ajhg.2012.02.026
Asharani, P V ; Keupp, Katharina ; Semler, Oliver ; Wang, Wenshen ; Li, Yun ; Thiele, Holger ; Yigit, Gokhan ; Pohl, Esther ; Becker, Jutta ; Frommolt, Peter ; Sonntag, Carmen ; Altmuller, Janine ; Zimmermann, Katharina ; Greenspan, Daniel S ; Akarsu, Nurten A ; Netzer, Christian ; Shonau, Eckhard ; Wirth, Radu ; Hammerschmidt, Matthias ; Nurnberg, Peter ; Wollnik, Bernd ; Carney, Thomas J. / Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish. In: American Journal of Human Genetics. 2012 ; Vol. 90, No. 4. pp. 661 - 674.
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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 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.",
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Asharani, PV, Keupp, K, Semler, O, Wang, W, Li, Y, Thiele, H, Yigit, G, Pohl, E, Becker, J, Frommolt, P, Sonntag, C, Altmuller, J, Zimmermann, K, Greenspan, DS, Akarsu, NA, Netzer, C, Shonau, E, Wirth, R, Hammerschmidt, M, Nurnberg, P, Wollnik, B & Carney, TJ 2012, 'Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish', American Journal of Human Genetics, vol. 90, no. 4, pp. 661 - 674. https://doi.org/10.1016/j.ajhg.2012.02.026

Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish. / Asharani, P V; Keupp, Katharina; Semler, Oliver; Wang, Wenshen; Li, Yun; Thiele, Holger; Yigit, Gokhan; Pohl, Esther; Becker, Jutta; Frommolt, Peter; Sonntag, Carmen; Altmuller, Janine; Zimmermann, Katharina; Greenspan, Daniel S; Akarsu, Nurten A; Netzer, Christian; Shonau, Eckhard; Wirth, Radu; Hammerschmidt, Matthias; Nurnberg, Peter; Wollnik, Bernd; Carney, Thomas J.

In: American Journal of Human Genetics, Vol. 90, No. 4, 2012, p. 661 - 674.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish

AU - Asharani, P V

AU - Keupp, Katharina

AU - Semler, Oliver

AU - Wang, Wenshen

AU - Li, Yun

AU - Thiele, Holger

AU - Yigit, Gokhan

AU - Pohl, Esther

AU - Becker, Jutta

AU - Frommolt, Peter

AU - Sonntag, Carmen

AU - Altmuller, Janine

AU - Zimmermann, Katharina

AU - Greenspan, Daniel S

AU - Akarsu, Nurten A

AU - Netzer, Christian

AU - Shonau, Eckhard

AU - Wirth, Radu

AU - Hammerschmidt, Matthias

AU - Nurnberg, Peter

AU - Wollnik, Bernd

AU - Carney, Thomas J

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22482805

U2 - 10.1016/j.ajhg.2012.02.026

DO - 10.1016/j.ajhg.2012.02.026

M3 - Article

VL - 90

SP - 661

EP - 674

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 4

ER -