title: MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta.
abstract: Osteogenesis imperfecta (OI) is a collagen-related bone dysplasia. We identified an X-linked recessive form of OI caused by defects in MBTPS2, which encodes site-2 metalloprotease (S2P). MBTPS2 missense mutations in two independent kindreds with moderate/severe OI cause substitutions at highly conserved S2P residues. Mutant S2P has normal stability, but impaired functioning in regulated intramembrane proteolysis (RIP) of OASIS, ATF6 and SREBP transcription factors, consistent with decreased proband secretion of type I collagen. Further, hydroxylation of the collagen lysine residue (K87) critical for crosslinking is reduced in proband bone tissue, consistent with decreased lysyl hydroxylase 1 in proband osteoblasts. Reduced collagen crosslinks presumptively undermine bone strength. Also, proband osteoblasts have broadly defective differentiation. These mutations provide evidence that RIP plays a fundamental role in normal bone development.
authors.affiliation: Division of Metabolism, Connective Tissue Unit and Children's Research Center, University Children's Hospital Zurich, Zurich 8032, Switzerland.
authors.forename: Uschi
authors.initials: U
authors.lastname: Lindert
authors.affiliation: Section on Heritable Disorders of Bone and Extracellular Matrix, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Cabral
authors.affiliation: Center of Excellence for Medical Genetics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.|Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok 10330, Thailand.
authors.forename: Surasawadee
authors.initials: S
authors.lastname: Ausavarat
authors.affiliation: Center of Excellence for Medical Genetics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.|Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok 10330, Thailand.
authors.forename: Siraprapa
authors.initials: S
authors.lastname: Tongkobpetch
authors.affiliation: Center for Laboratory Medicine, Department of Medical Genetics, Kantonsspital Aarau, Aarau 5001, Switzerland.
authors.forename: Katja
authors.initials: K
authors.lastname: Ludin
authors.affiliation: Section on Heritable Disorders of Bone and Extracellular Matrix, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Aileen M
authors.initials: AM
authors.lastname: Barnes
authors.affiliation: Center of Excellence for Medical Genetics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.|Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok 10330, Thailand.
authors.forename: Patra
authors.initials: P
authors.lastname: Yeetong
authors.affiliation: Department of Orthopedics and Sports Medicine, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Maryann
authors.initials: M
authors.lastname: Weis
authors.affiliation: Division of Human Genetics, Medical University of Innsbruck, Innsbruck 6020, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Krabichler
authors.affiliation: Center of Excellence for Medical Genetics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.|Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok 10330, Thailand.
authors.forename: Chalurmpon
authors.initials: C
authors.lastname: Srichomthong
authors.affiliation: Section on Physical Biochemistry, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Elena N
authors.initials: EN
authors.lastname: Makareeva
authors.affiliation: Division of Human Genetics, Medical University of Innsbruck, Innsbruck 6020, Austria.|Department of Pediatrics I, Medical University of Innsbruck, Innsbruck 6020, Austria.
authors.forename: Andreas R
authors.identifier: http://orcid.org/0000-0001-7155-0315
authors.initials: AR
authors.lastname: Janecke
authors.affiliation: Section on Physical Biochemistry, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Leikin
authors.affiliation: Center for Laboratory Medicine, Department of Medical Genetics, Kantonsspital Aarau, Aarau 5001, Switzerland.
authors.forename: Benno
authors.initials: B
authors.lastname: Röthlisberger
authors.affiliation: Division of Metabolism, Connective Tissue Unit and Children's Research Center, University Children's Hospital Zurich, Zurich 8032, Switzerland.
authors.forename: Marianne
authors.initials: M
authors.lastname: Rohrbach
authors.affiliation: Institute of Human Genetics, Westfälische Wilhelms University, Münster 48149, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Kennerknecht
authors.affiliation: Department of Orthopedics and Sports Medicine, University of Washington, Seattle, Washington 98195, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Eyre
authors.affiliation: Center of Excellence for Medical Genetics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.|Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok 10330, Thailand.
authors.forename: Kanya
authors.initials: K
authors.lastname: Suphapeetiporn
authors.affiliation: Division of Metabolism, Connective Tissue Unit and Children's Research Center, University Children's Hospital Zurich, Zurich 8032, Switzerland.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Giunta
authors.affiliation: Section on Heritable Disorders of Bone and Extracellular Matrix, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Joan C
authors.initials: JC
authors.lastname: Marini
authors.affiliation: Center of Excellence for Medical Genetics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.|Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok 10330, Thailand.
authors.forename: Vorasuk
authors.identifier: http://orcid.org/0000-0002-1856-0589
authors.initials: V
authors.lastname: Shotelersuk
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism / Q000473:pathology*; D024042:Collagen Type I / Q000172:deficiency / Q000235:genetics*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005808:Genes, Recessive; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D010013:Osteogenesis Imperfecta / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D012720:Severity of Illness Index; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; C485618:CREB3L1 protein, human; D024042:Collagen Type I; D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D051779:Sterol Regulatory Element Binding Proteins; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; C500142:lysyl hydroxylase 1, human; D008666:Metalloendopeptidases; C120654:MBTPS2 protein, human