uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
COL1 C-Propeptide Cleavage Site Mutations Cause High Bone Mass Osteogenesis Imperfecta
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Show others and affiliations
2011 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 32, no 6, 598-609 p.Article in journal (Refereed) Published
Abstract [en]

Osteogenesis imperfecta (OI) is most often caused by mutations in the type I procollagen genes (COL1A1/COL1A2). We identified two children with substitutions in the type I procollagen C-propeptide cleavage site, which disrupt a unique processing step in collagen maturation and define a novel phenotype within OI. The patients have mild OI caused by mutations in COL1A1 (Patient 1: p.Asp1219Asn) or COL1A2 (Patient 2: p.Ala1119Thr), respectively. Patient 1 L1-L4 DXA Z-score was +3.9 and pQCT vBMD was +3.1; Patient 2 had L1-L4 DXA Z-score of 0.0 and pQCT vBMD of -1.8. Patient BMD contrasts with radiographic osteopenia and histomorphometry without osteosclerosis. Mutant procollagen processing is impaired in pericellular and in vitro assays. Patient dermal collagen fibrils have irregular borders. Incorporation of pC-collagen into matrix leads to increased bone mineralization. FTIR imaging confirms elevated mineral/matrix ratios in both patients, along with increased collagen maturation in trabecular bone, compared to normal or OI controls. Bone mineralization density distribution revealed a marked shift toward increased mineralization density for both patients. Patient 1 has areas of higher and lower bone mineralization than controls; Patient 2's bone matrix has a mineral content exceeding even classical OI bone. These patients define a new phenotype of high BMD OI and demonstrate that procollagen C-propeptide cleavage is crucial to normal bone mineralization.

Place, publisher, year, edition, pages
2011. Vol. 32, no 6, 598-609 p.
Keyword [en]
osteogenesis imperfecta, C-propeptide, collagen, C-proteinase, mineralization, high bone mass
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-155592DOI: 10.1002/humu.21475ISI: 000291564000011OAI: oai:DiVA.org:uu-155592DiVA: diva2:427399
Available from: 2011-06-28 Created: 2011-06-27 Last updated: 2013-12-05Bibliographically approved
In thesis
1. Osteogenesis Imperfecta: Genetic and Therapeutic Studies
Open this publication in new window or tab >>Osteogenesis Imperfecta: Genetic and Therapeutic Studies
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Osteogenesis imperfecta (OI) is a heterogeneous disease of connective tissue, the cardinal symptom being fractures and severity ranging from mild to lethal. Dominant mutations in collagen I, encoded by COL1A1 and COL1A2, cause >90% of cases.

To delineate genotype-phenotype correlations and pharmaco-genetic response, collagen I was sequenced in 150 unrelated Swedish families and clinical data were collected in Paper I. Mutation type, gene affected, and N- to C-terminal location correlated with phenotype and severity. Bisphosphonate response assessed by calculated yearly change in lumbar spine bone mineral density (BMD) was inversely related to age and BMD at treatment initiation. Mutations associated with a more severe phenotype exhibited an increased response after 2 years; however, all types of OI responded well.

To investigate the effect of naturally occurring variations in collagen I, the only common coding single nucleotide polymorphism (rs42524 in COL1A2) was genotyped in 2004 healthy men in Paper II. Heterozygous genotype was associated with decreased BMD and an increased risk of stroke.

An adolescent with repeated fractures despite a markedly high BMD harbored a unique C-terminal procollagen cleavage-site mutation in COL1A1, which motivated extensive investigations in concert with a similar COL1A2 case in Paper III. The probands were found to have impaired procollagen processing, incorporation of collagen with retained C-propeptide in matrix and increased mineral to matrix ratio, which demonstrates that C-propeptide cleavage is crucial to normal bone mineralization and structure.

Bisphosphonate therapy has insufficient effect in OI, and as classical OI is a dominant disorder severe cases would benefit from silencing of the mutated allele. In Paper IV and V small interfering RNAs (siRNAs) were used to allele-specifically target primary human bone cells heterozygous for I) a coding polymorphism in COL1A2 and II) insertion/deletions in the 3’UTR of COL1A1 and COL1A2. Results were promising with altered allele ratios and decreased mRNA levels in the predicted fashion.

To summarize, this thesis found that collagen I is crucial to bone and connective tissue and that collagen I mutations create markedly diverse phenotypes. Age, BMD and pharmaco-genetic effects influence the response to bisphosphonate therapy in individuals with OI; however, novel approaches are needed. Utilizing allele-specific siRNAs may be a way forward in the treatment of severe OI.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 96 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 936
Keyword
OI, BMD, Genotype, Phenotype, Pharmaco-genetics, Bisphosphonate, Therapy, Gene-therapy, Mutation, Collagen, Collagen type I, Allele-specific silencing, siRNA, RNAi, COL1A1, COL1A2, Stroke, C-propeptide, Mineralization, Heterozygous disadvantage
National Category
Endocrinology and Diabetes
Research subject
Genetics; Medicine; Medical Genetics
Identifiers
urn:nbn:se:uu:diva-208942 (URN)978-91-554-8772-0 (ISBN)
Public defence
2013-11-29, Enghoffsalen, Ingång 50, Akademiska Sjukhuset, Uppsala, 09:15 (English)
Opponent
Supervisors
Funder
Swedish Research Council
Available from: 2013-11-08 Created: 2013-10-11 Last updated: 2014-01-23

Open Access in DiVA

No full text

Other links

Publisher's full text
By organisation
Department of Medical SciencesDepartment of Medical Biochemistry and Microbiology
In the same journal
Human Mutation
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

Altmetric score

Total: 302 hits
ReferencesLink to record
Permanent link

Direct link