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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta
Human Mutation, Volume 33, No. 2, Year 2012
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Description
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. © 2011 Wiley Periodicals, Inc.
Authors & Co-Authors
Mart́inez-Glez, V́ictor
Spain, Madrid
Instituto de Salud Carlos Iii
Spain, Madrid
Instituto de Investigación Sanitaria Del Hospital Universitario la Paz
Valencia, Maria
Spain, Madrid
Instituto de Salud Carlos Iii
Spain, Madrid
Consejo Superior de Investigaciones Científicas
Caparros-Martin, José A.
Spain, Madrid
Instituto de Salud Carlos Iii
Spain, Madrid
Consejo Superior de Investigaciones Científicas
Aglan, Mona Sabry
Egypt, Giza
National Research Centre
Temtamy, Samia Ali Li
Egypt, Giza
National Research Centre
Tenorio, Jair
Spain, Madrid
Instituto de Investigación Sanitaria Del Hospital Universitario la Paz
Pulido, Veronica
Spain, Madrid
Consejo Superior de Investigaciones Científicas
Lindert, Uschi
Switzerland, Zurich
Kinderspital Zürich
Rohrbach, Marianne
Switzerland, Zurich
Kinderspital Zürich
Eyre, David
United States, Seattle
University of Washington
Giunta, Cecilia
Switzerland, Zurich
Kinderspital Zürich
Lapunzina-Badía, Pablo Daniel
Spain, Madrid
Instituto de Salud Carlos Iii
Spain, Madrid
Instituto de Investigación Sanitaria Del Hospital Universitario la Paz
Ruiz-Perez, Victor L.
Spain, Madrid
Instituto de Salud Carlos Iii
Spain, Madrid
Consejo Superior de Investigaciones Científicas
Statistics
Citations: 194
Authors: 13
Affiliations: 6
Identifiers
Doi:
10.1002/humu.21647
ISSN:
10597794
e-ISSN:
10981004
Research Areas
Cancer
Genetics And Genomics
Health System And Policy
Maternal And Child Health