Nature communications · 2016
MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta.
СтатьяПоддержка NIH: внешняя программаResearch Support, N.I.H., IntramuralПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Lindert Uschi, Cabral Wayne A, Ausavarat Surasawadee, Tongkobpetch Siraprapa, Ludin Katja, Barnes Aileen M, Yeetong Patra, Weis Maryann, Krabichler Birgit, Srichomthong Chalurmpon, Makareeva Elena N, Janecke Andreas R, Leikin Sergey, Röthlisberger Benno, Rohrbach Marianne, Kennerknecht Ingo, Eyre David R, Suphapeetiporn Kanya, Giunta Cecilia, Marini Joan C, Shotelersuk Vorasuk
Аннотация
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.
Предметные рубрики MeSH
Activating Transcription Factor 6AdultAgedCell DifferentiationCell MembraneCollagen Type ICyclic AMP Response Element-Binding ProteinGene Expression RegulationGenes, RecessiveHumansHydroxylationMaleMetalloendopeptidasesMiddle AgedMutation, MissenseNerve Tissue ProteinsOsteoblastsOsteogenesis ImperfectaPedigreeProcollagen-Lysine, 2-Oxoglutarate 5-DioxygenaseProteolysisSeverity of Illness IndexSterol Regulatory Element Binding Proteins