title: Defective Proteolytic Processing of Fibrillar Procollagens and Prodecorin Due to Biallelic BMP1 Mutations Results in a Severe, Progressive Form of Osteogenesis Imperfecta.
abstract: Whereas the vast majority of osteogenesis imperfecta (OI) is caused by autosomal dominant defects in the genes encoding type I procollagen, mutations in a myriad of genes affecting type I procollagen biosynthesis or bone formation and homeostasis have now been associated with rare autosomal recessive OI forms. Recently, homozygous or compound heterozygous mutations in BMP1, encoding the metalloproteases bone morphogenetic protein-1 (BMP1) and its longer isoform mammalian Tolloid (mTLD), were identified in 5 children with a severe autosomal recessive form of OI and in 4 individuals with mild to moderate bone fragility. BMP1/mTLD functions as the procollagen carboxy-(C)-proteinase for types I to III procollagen but was also suggested to participate in amino-(N)-propeptide cleavage of types V and XI procollagens and in proteolytic trimming of other extracellular matrix (ECM) substrates. We report the phenotypic characteristics and natural history of 4 adults with severe, progressive OI characterized by numerous fractures, short stature with rhizomelic shortening, and deformity of the limbs and variable kyphoscoliosis, in whom we identified novel biallelic missense and frameshift mutations in BMP1. We show that BMP1/mTLD-deficiency in humans not only results in delayed cleavage of the type I procollagen C-propeptide but also hampers the processing of the small leucine-rich proteoglycan prodecorin, a regulator of collagen fibrillogenesis. Immunofluorescent staining of types I and V collagen and transmission electron microscopy of the dermis show impaired assembly of heterotypic type I/V collagen fibrils in the ECM. Our study thus highlights the severe and progressive nature of BMP1-associated OI in adults and broadens insights into the functional consequences of BMP1/mTLD-deficiency on ECM organization.
authors: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors: Delfien
authors: D
authors: Syx
authors: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors: Brecht
authors: B
authors: Guillemyn
authors: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors: Sofie
authors: S
authors: Symoens
authors: Department of Genetics, Hospital de Santa Maria de Lisboa, Lisbon, Portugal.
authors: Ana Berta
authors: AB
authors: Sousa
authors: Department of Genetics, Hospital de Santa Maria de Lisboa, Lisbon, Portugal.
authors: Ana
authors: A
authors: Medeira
authors: Department of Clinical Genetics, Southern General Hospital, Glasgow, United Kingdom.
authors: Margo
authors: M
authors: Whiteford
authors: Department of Dermatopathology, Liège University Hospital, Liège, Belgium.
authors: Trinh
authors: T
authors: Hermanns-Lê
authors: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors: Paul J
authors: PJ
authors: Coucke
authors: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors: Anne
authors: A
authors: De Paepe
authors: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors: Fransiska
authors: F
authors: Malfait
mesh_terms: D000328:Adult; D000483:Alleles; D055395:Bone Morphogenetic Protein 1 / Q000235:genetics / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024062:Collagen Type V / Q000235:genetics / Q000378:metabolism; D058575:Decorin / Q000235:genetics / Q000378:metabolism; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011347:Procollagen / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis
chemical_list: D024042:Collagen Type I; D024062:Collagen Type V; C546878:DCN protein, human; D058575:Decorin; D011347:Procollagen; C525705:BMP1 protein, human; D055395:Bone Morphogenetic Protein 1
keywords: BMP1; BONE MORPHOGENETIC PROTEIN-1; MAMMALIAN TOLLOID; OSTEOGENESIS IMPERFECTA; PRODECORIN