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      Mutations in COL1A1 and COL1A2 and dental aberrations in children and adolescents with osteogenesis imperfecta – A retrospective cohort study

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          Abstract

          Osteogenesis imperfecta (OI) is a heterogeneous group of disorders of connective tissue, caused mainly by mutations in the collagen I genes ( COL1A1 and COL1A2). Dentinogenesis imperfecta (DGI) and other dental aberrations are common features of OI. We investigated the association between collagen I mutations and DGI, taurodontism, and retention of permanent second molars in a retrospective cohort of 152 unrelated children and adolescents with OI. The clinical examination included radiographic evaluations. Teeth from 81 individuals were available for histopathological evaluation. COL1A1/2 mutations were found in 104 individuals by nucleotide sequencing. DGI was diagnosed clinically and radiographically in 29% of the individuals (44/152) and through isolated histological findings in another 19% (29/152). In the individuals with a COL1A1 mutation, 70% (7/10) of those with a glycine substitution located C-terminal of p.Gly305 exhibited DGI in both dentitions while no individual (0/7) with a mutation N-terminal of this point exhibited DGI in either dentition (p = 0.01). In the individuals with a COL1A2 mutation, 80% (8/10) of those with a glycine substitution located C terminal of p.Gly211 exhibited DGI in both dentitions while no individual (0/5) with a mutation N-terminal of this point (p = 0.007) exhibited DGI in either dentition. DGI was restricted to the deciduous dentition in 20 individuals. Seventeen had missense mutations where glycine to serine was the most prevalent substitution (53%). Taurodontism occurred in 18% and retention of permanent second molars in 31% of the adolescents. Dental aberrations are strongly associated with qualitatively changed collagen I. The varying expressivity of DGI is related to the location of the collagen I mutation. Genotype information may be helpful in identifying individuals with OI who have an increased risk of dental aberrations.

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          Genetic heterogeneity in osteogenesis imperfecta.

          D Sillence, A Senn, D M Danks (1979)
          An epidemiological and genetical study of osteogenesis imperfecta (OI) in Victoria, Australia confirmed that there are at least four distinct syndromes at present called OI. The largest group of patients showed autosomal dominant inheritance of osteoporosis leading to fractures and distinctly blue sclerae. A large proportion of adults had presenile deafness or a family history of presenile conductive hearing loss. A second group, who comprised the majority of newborns with neonatal fractures, all died before or soon after birth. These had characteristic broad, crumpled femora and beaded ribs in skeletal x-rays. Autosomal recessive inheritance was likely for some, if not all, of these cases. A third group, two thirds of whom had fractures at birth, showed severe progressive deformity of limbs and spine. The density of scleral blueness appeared less than that seen in the first group of patients and approximated that seen in normal children and adults. Moreover, the blueness appeared to decrease with age. All patients in this group were sporadic cases. The mode of inheritance was not resolved by the study, but it is likely that the group is heterogeneous with both dominant and recessive genotypes responsible for the syndrome. The fourth group of patients showed dominant inheritance of osteoporosis leading to fractures, with variable deformity of long bones, but normal sclerae.
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            Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans.

            Joan C. Marini, Antonella Forlino, Wayne Cabral … (2007)
            Osteogenesis imperfecta (OI) is a generalized disorder of connective tissue characterized by fragile bones and easy susceptibility to fracture. Most cases of OI are caused by mutations in type I collagen. We have identified and assembled structural mutations in type I collagen genes (COL1A1 and COL1A2, encoding the proalpha1(I) and proalpha2(I) chains, respectively) that result in OI. Quantitative defects causing type I OI were not included. Of these 832 independent mutations, 682 result in substitution for glycine residues in the triple helical domain of the encoded protein and 150 alter splice sites. Distinct genotype-phenotype relationships emerge for each chain. One-third of the mutations that result in glycine substitutions in alpha1(I) are lethal, especially when the substituting residues are charged or have a branched side chain. Substitutions in the first 200 residues are nonlethal and have variable outcome thereafter, unrelated to folding or helix stability domains. Two exclusively lethal regions (helix positions 691-823 and 910-964) align with major ligand binding regions (MLBRs), suggesting crucial interactions of collagen monomers or fibrils with integrins, matrix metalloproteinases (MMPs), fibronectin, and cartilage oligomeric matrix protein (COMP). Mutations in COL1A2 are predominantly nonlethal (80%). Lethal substitutions are located in eight regularly spaced clusters along the chain, supporting a regional model. The lethal regions align with proteoglycan binding sites along the fibril, suggesting a role in fibril-matrix interactions. Recurrences at the same site in alpha2(I) are generally concordant for outcome, unlike alpha1(I). Splice site mutations comprise 20% of helical mutations identified in OI patients, and may lead to exon skipping, intron inclusion, or the activation of cryptic splice sites. Splice site mutations in COL1A1 are rarely lethal; they often lead to frameshifts and the mild type I phenotype. In alpha2(I), lethal exon skipping events are located in the carboxyl half of the chain. Our data on genotype-phenotype relationships indicate that the two collagen chains play very different roles in matrix integrity and that phenotype depends on intracellular and extracellular events.
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              Cyclic administration of pamidronate in children with severe osteogenesis imperfecta.

              F Glorieux, N. Bishop, H Plotkin … (1998)
              Severe osteogenesis imperfecta is a disorder characterized by osteopenia, frequent fractures, progressive deformity, loss of mobility, and chronic bone pain. There is no effective therapy for the disorder. We assessed the effects of treatment with a bisphosphonate on bone resorption. In an uncontrolled observational study involving 30 children who were 3 to 16 years old and had severe osteogenesis imperfecta, we administered pamidronate intravenously (mean [+/-SD] dose, 6.8+/-1.1 mg per kilogram of body weight per year) at 4-to-6-month intervals for 1.3 to 5.0 years. Clinical status, biochemical characteristics reflecting bone turnover, the bone mineral density of the lumbar spine, and radiologic changes were assessed regularly during treatment. Administration of pamidronate resulted in sustained reductions in serum alkaline phosphatase concentrations and in the urinary excretion of calcium and type I collagen N-telopeptide. There was a mean annualized increase of 41.9+/-29.0 percent in bone mineral density, and the deviation of bone mineral density from normal, as indicated by the z score, improved from -5.3+/-1.2 to -3.4+/-1.5. The cortical width of the metacarpals increased by 27+/-20.2 percent per year. The increases in the size of the vertebral bodies suggested that new bone had formed. The mean incidence of radiologically confirmed fractures decreased by 1.7 per year (P<0.001). Treatment with pamidronate did not alter the rate of fracture healing, the growth rate, or the appearance of the growth plates. Mobility and ambulation improved in 16 children and remained unchanged in the other 14. All the children reported substantial relief of chronic pain and fatigue. In children with severe osteogenesis imperfecta, cyclic administration of intravenous pamidronate improved clinical outcomes, reduced bone resorption, and increased bone density.
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                Author and article information

                Contributors
                Kimon Divaris: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 12 May 2017
                Publication date Collection: 2017
                Volume: 12
                Issue: 5
                Electronic Location Identifier: e0176466
                Affiliations
                [1 ]Department of Dental Medicine, Division of Pediatric Dentistry, Karolinska Institutet, Huddinge, Sweden
                [2 ]Center for Pediatric Oral Health Research, Stockholm, Sweden
                [3 ]Department of Medical Sciences, Uppsala University, Uppsala, Sweden
                [4 ]Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
                [5 ]Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
                [6 ]Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden
                [7 ]Pediatric Neurology and Musculoskeletal disorders and Home care, Astrid Lindgren Children's Hospital at Karolinska University Hospital, Stockholm, Sweden
                University of North Carolina at Chapel Hill, UNITED STATES
                Author notes

                Competing Interests: The authors declare no competing interests.

                • Conceptualization: GD EÅ BM.

                • Data curation: KA KL AK GG EÅ BM.

                • Formal analysis: KA GD KL GG EÅ BM.

                • Funding acquisition: KA GD KL AK GG EÅ.

                • Investigation: KA KL AK GG EÅ BM.

                • Methodology: GD EÅ BM.

                • Project administration: BM.

                • Resources: KA KL EÅ BM.

                • Supervision: GD EÅ BM.

                • Validation: KA GD KL AK GG EÅ BM.

                • Visualization: KA BM.

                • Writing – original draft: KA GD EÅ BM.

                • Writing – review & editing: KA GD KL AK GG EÅ BM.

                Author information
                http://orcid.org/0000-0001-8366-8804
                Article
                Publisher ID: PONE-D-16-50023
                DOI: 10.1371/journal.pone.0176466
                PMC ID: 5428910
                PubMed ID: 28498836
                SO-VID: 3c207f08-bd01-4572-9e61-b91eb7b64848
                Copyright © © 2017 Andersson et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 19 December 2016
                Date accepted : 11 April 2017
                Page count
                Figures: 8, Tables: 1, Pages: 16
                Funding
                Funded by: Uppsala County Council (ALF project)
                Award Recipient :
                Funded by: Stockholm County Council (ALF project)
                Award Recipient :
                Funded by: American Dental Society of Sweden (ADSS)
                Award Recipient :
                ORCID: http://orcid.org/0000-0001-8366-8804
                Funded by: funder-id http://dx.doi.org/10.13039/501100005301, Svenska Tandläkare-Sällskapet;
                Award Recipient :
                ORCID: http://orcid.org/0000-0001-8366-8804
                Funded by: Swedish Endocrine Society
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100009389, Stiftelsen Promobilia;
                Award Recipient :
                Funded by: Stockholm County Council (ALF project)
                Award Recipient :
                KA has been supported by grants from the American Dental Society of Sweden (ADSS) ( http://www.adss.se/) and Svenska Tandläkare-Sällskapet ( https://tandlakarforbundet.se/forskning/svenska-tandlakare-sallskapet/); and KL was supported by the Swedish Endocrine Society ( http://endokrinologforeningen.se/). AK received grants from Uppsala County Council (ALF project). GG has been supported by Stiftelsen Promobilia ( http://www.promobilia.se) and Stockholm County Council (ALF project). EÅ has been supported by Stockholm County Council (ALF project). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Digestive Physiology
                Subject: Dentition
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Digestive Physiology
                Subject: Dentition
                Subject: Medicine and Health Sciences
                Subject: Rheumatology
                Subject: Connective Tissue Diseases
                Subject: Collagen Diseases
                Subject: Osteogenesis Imperfecta
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Digestive System
                Subject: Teeth
                Subject: Molars
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Digestive System
                Subject: Teeth
                Subject: Molars
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Head
                Subject: Jaw
                Subject: Teeth
                Subject: Molars
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Head
                Subject: Jaw
                Subject: Teeth
                Subject: Molars
                Subject: Biology and Life Sciences
                Subject: Genetics
                Subject: Mutation
                Subject: Substitution Mutation
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Proteins
                Subject: Collagens
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Chemical Compounds
                Subject: Organic Compounds
                Subject: Amino Acids
                Subject: Aliphatic Amino Acids
                Subject: Glycine
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Organic Chemistry
                Subject: Organic Compounds
                Subject: Amino Acids
                Subject: Aliphatic Amino Acids
                Subject: Glycine
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Proteins
                Subject: Amino Acids
                Subject: Aliphatic Amino Acids
                Subject: Glycine
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Digestive System
                Subject: Teeth
                Subject: Dentin
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Digestive System
                Subject: Teeth
                Subject: Dentin
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Head
                Subject: Jaw
                Subject: Teeth
                Subject: Dentin
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Head
                Subject: Jaw
                Subject: Teeth
                Subject: Dentin
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Histology
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Histology
                Custom metadata
                Data Availability The dataset generated during the current study is available in the Dryad Digital Repository ( https://datadryad.org), DOI: http://dx.doi.org/10.5061/dryad.bp20k. Mutations are available from NCBI ClinVar: SCV000574569 - SCV000574676.

                ScienceOpen disciplines: Uncategorized
                Data availability:
                ScienceOpen disciplines: Uncategorized

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