MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta

Uschi Lindert; Wayne A Cabral; Surasawadee Ausavarat; Siraprapa Tongkobpetch; Katja Ludin; Aileen M Barnes; Patra Yeetong; Maryann Weis; Birgit Krabichler; Chalurmpon Srichomthong; Elena N Makareeva; Andreas R Janecke; Sergey Leikin; Benno Röthlisberger; Marianne Rohrbach; Ingo Kennerknecht; David R Eyre; Kanya Suphapeetiporn; Cecilia Giunta; Joan C Marini; Vorasuk Shotelersuk

doi:10.1038/ncomms11920

MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta

Nat Commun. 2016 Jul 6:7:11920. doi: 10.1038/ncomms11920.

Authors

Uschi Lindert¹, Wayne A Cabral², Surasawadee Ausavarat^{3

4}, Siraprapa Tongkobpetch^{3

4}, Katja Ludin⁵, Aileen M Barnes², Patra Yeetong^{3

4}, Maryann Weis⁶, Birgit Krabichler⁷, Chalurmpon Srichomthong^{3

4}, Elena N Makareeva⁸, Andreas R Janecke^{7

9}, Sergey Leikin⁸, Benno Röthlisberger⁵, Marianne Rohrbach¹, Ingo Kennerknecht¹⁰, David R Eyre⁶, Kanya Suphapeetiporn^{3

4}, Cecilia Giunta¹, Joan C Marini², Vorasuk Shotelersuk^{3

4}

Affiliations

¹ Division of Metabolism, Connective Tissue Unit and Children's Research Center, University Children's Hospital Zurich, Zurich 8032, Switzerland.
² 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.
³ Center of Excellence for Medical Genetics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
⁴ Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok 10330, Thailand.
⁵ Center for Laboratory Medicine, Department of Medical Genetics, Kantonsspital Aarau, Aarau 5001, Switzerland.
⁶ Department of Orthopedics and Sports Medicine, University of Washington, Seattle, Washington 98195, USA.
⁷ Division of Human Genetics, Medical University of Innsbruck, Innsbruck 6020, Austria.
⁸ Section on Physical Biochemistry, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
⁹ Department of Pediatrics I, Medical University of Innsbruck, Innsbruck 6020, Austria.
¹⁰ Institute of Human Genetics, Westfälische Wilhelms University, Münster 48149, Germany.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Activating Transcription Factor 6 / genetics
Activating Transcription Factor 6 / metabolism
Adult
Aged
Cell Differentiation
Cell Membrane / metabolism
Cell Membrane / pathology*
Collagen Type I / deficiency
Collagen Type I / genetics*
Cyclic AMP Response Element-Binding Protein / genetics
Cyclic AMP Response Element-Binding Protein / metabolism
Gene Expression Regulation
Genes, Recessive
Humans
Hydroxylation
Male
Metalloendopeptidases / genetics*
Metalloendopeptidases / metabolism
Middle Aged
Mutation, Missense*
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism
Osteoblasts / metabolism*
Osteoblasts / pathology
Osteogenesis Imperfecta / genetics*
Osteogenesis Imperfecta / metabolism
Osteogenesis Imperfecta / pathology
Pedigree
Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / genetics
Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / metabolism
Proteolysis
Severity of Illness Index
Sterol Regulatory Element Binding Proteins / genetics
Sterol Regulatory Element Binding Proteins / metabolism

Substances

ATF6 protein, human
Activating Transcription Factor 6
CREB3L1 protein, human
Collagen Type I
Cyclic AMP Response Element-Binding Protein
Nerve Tissue Proteins
Sterol Regulatory Element Binding Proteins
Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase
lysyl hydroxylase 1, human
Metalloendopeptidases
MBTPS2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding