title: Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta.
abstract: Herein, we have studied a consanguineous Egyptian family with two children diagnosed with severe autosomal recessive osteogenesis imperfecta (AR-OI) and a large umbilical hernia. Homozygosity mapping in this family showed lack of linkage to any of the previously known AR-OI genes, but revealed a 10.27 MB homozygous region on chromosome 8p in the two affected sibs, which comprised the procollagen I C-terminal propeptide (PICP) endopeptidase gene BMP1. Mutation analysis identified both patients with a Phe249Leu homozygous missense change within the BMP1 protease domain involving a residue, which is conserved in all members of the astacin group of metalloproteases. Type I procollagen analysis in supernatants from cultured fibroblasts demonstrated abnormal PICP processing in patient-derived cells consistent with the mutation causing decreased BMP1 function. This was further confirmed by overexpressing wild type and mutant BMP1 longer isoform (mammalian Tolloid protein [mTLD]) in NIH3T3 fibroblasts and human primary fibroblasts. While overproduction of normal mTLD resulted in a large proportion of proα1(I) in the culture media being C-terminally processed, proα1(I) cleavage was not enhanced by an excess of the mutant protein, proving that the Phe249Leu mutation leads to a BMP1/mTLD protein with deficient PICP proteolytic activity. We conclude that BMP1 is an additional gene mutated in AR-OI.
authors: Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain.
authors: Víctor
authors: V
authors: Martínez-Glez
authors: Maria
authors: M
authors: Valencia
authors: José A
authors: JA
authors: Caparrós-Martín
authors: Mona
authors: M
authors: Aglan
authors: Samia
authors: S
authors: Temtamy
authors: Jair
authors: J
authors: Tenorio
authors: Veronica
authors: V
authors: Pulido
authors: Uschi
authors: U
authors: Lindert
authors: Marianne
authors: M
authors: Rohrbach
authors: David
authors: D
authors: Eyre
authors: Cecilia
authors: C
authors: Giunta
authors: Pablo
authors: P
authors: Lapunzina
authors: Victor L
authors: VL
authors: Ruiz-Perez
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D055395:Bone Morphogenetic Protein 1 / Q000172:deficiency / Q000235:genetics*; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D005808:Genes, Recessive; D057809:HEK293 Cells; D006720:Homozygote; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D041681:NIH 3T3 Cells; D010013:Osteogenesis Imperfecta / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D059748:Proteolysis; D016415:Sequence Alignment; D012801:Sibling Relations
chemical_list: D007527:Isoenzymes; D055395:Bone Morphogenetic Protein 1