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Recessive osteogenesis imperfecta caused by missense mutations in SPARC.
Mendoza-Londono R, Fahiminiya S, Majewski J, Care4Rare Canada Consortium, Tétreault M, Nadaf J, Kannu P, Sochett E, Howard A, Stimec J, Dupuis L, Roschger P, Klaushofer K, Palomo T, Ouellet J, Al-Jallad H, Mort JS, Moffatt P, Boudko S, Bächinger HP, Rauch F
(2015) Am J Hum Genet 96: 979-85
MeSH Terms: Amino Acid Sequence, Base Sequence, Collagen Type I, Electrophoresis, Polyacrylamide Gel, Exome, Female, Genes, Recessive, Humans, Immunoblotting, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Mutation, Missense, Osteogenesis Imperfecta, Osteonectin, Pedigree, Protein Conformation, Sequence Alignment, Sequence Analysis, DNA
Show Abstract · Added November 2, 2017
Secreted protein, acidic, cysteine-rich (SPARC) is a glycoprotein that binds to collagen type I and other proteins in the extracellular matrix. Using whole-exome sequencing to identify the molecular defect in two unrelated girls with severe bone fragility and a clinical diagnosis of osteogenesis imperfecta type IV, we identified two homozygous variants in SPARC (GenBank: NM_003118.3; c.497G>A [p.Arg166His] in individual 1; c.787G>A [p.Glu263Lys] in individual 2). Published modeling and site-directed mutagenesis studies had previously shown that the residues substituted by these mutations form an intramolecular salt bridge in SPARC and are essential for the binding of SPARC to collagen type I. The amount of SPARC secreted by skin fibroblasts was reduced in individual 1 but appeared normal in individual 2. The migration of collagen type I alpha chains produced by these fibroblasts was mildly delayed on SDS-PAGE gel, suggesting some overmodification of collagen during triple helical formation. Pulse-chase experiments showed that collagen type I secretion was mildly delayed in skin fibroblasts from both individuals. Analysis of an iliac bone sample from individual 2 showed that trabecular bone was hypermineralized on the material level. In conclusion, these observations show that homozygous mutations in SPARC can give rise to severe bone fragility in humans.
Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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19 MeSH Terms
Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB.
Rauch F, Fahiminiya S, Majewski J, Carrot-Zhang J, Boudko S, Glorieux F, Mort JS, Bächinger HP, Moffatt P
(2015) Am J Hum Genet 96: 425-31
MeSH Terms: Child, Preschool, Craniosynostoses, Eye Abnormalities, Female, Gene Frequency, Heterozygote, Humans, Hydrocephalus, Infant, Male, Mutation, Missense, Osteogenesis Imperfecta, Pedigree, Procollagen-Proline Dioxygenase, Protein Conformation, Protein Disulfide-Isomerases, Protein Folding, Sequence Analysis, DNA
Show Abstract · Added November 2, 2017
Cole-Carpenter syndrome is a severe bone fragility disorder that is characterized by frequent fractures, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features. To identify the cause of Cole-Carpenter syndrome in the two individuals whose clinical results were presented in the original description of this disorder, we performed whole-exome sequencing of genomic DNA samples from both individuals. The two unrelated individuals had the same heterozygous missense mutation in exon 9 of P4HB (NM_000918.3: c.1178A>G [p.Tyr393Cys]), the gene that encodes protein disulfide isomerase (PDI). In one individual, the P4HB mutation had arisen de novo, whereas in the other the mutation was transmitted from the clinically unaffected father who was a mosaic carrier of the variant. The mutation was located in the C-terminal disulfide isomerase domain of PDI, sterically close to the enzymatic center, and affected disulfide isomerase activity in vitro. Skin fibroblasts showed signs of increased endoplasmic reticulum stress, but despite the reported importance of PDI for collagen type I production, the rate of collagen type I secretion appeared normal. In conclusion, Cole-Carpenter syndrome is caused by a specific de novo mutation in P4HB that impairs the disulfide isomerase activity of PDI.
Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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18 MeSH Terms
A huge coronary artery aneurysm in osteogenesis imperfecta: a case report.
Hajsadeghi S, Jafarian Kerman SR, Pouraliakbar H, Mohammadi R
(2012) Acta Med Iran 50: 785-8
MeSH Terms: Adult, Anti-Inflammatory Agents, Non-Steroidal, Aspirin, Clopidogrel, Coronary Aneurysm, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Hypotension, Inferior Wall Myocardial Infarction, Osteogenesis Imperfecta, Platelet Aggregation Inhibitors, Rare Diseases, Ticlopidine, Treatment Outcome, Ultrasonography
Show Abstract · Added April 25, 2016
Osteogenesis imperfecta (OI) as an inherited connective tissue disorder can affect all tissues that contains type I collagen. Well-known cardiac complications of this disease such as aortic root dilatation, aortic regurgitation and mitral valve prolapse have been rarely reported in the literature. Coronary artery aneurysm is a rare cardiac complication in OI, as reported in a 19 year old female presenting with myocardial infarction and hypotension.
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17 MeSH Terms