Unequal Impact of COL1A1 and COL1A2 Variants on Dentinogenesis Imperfecta

Author:

Yamaguti P.M.12,de La Dure-Molla M.345,Monnot S.67,Cardozo-Amaya Y.J.128,Baujat G.67,Michot C.67,Fournier B.P.J.349,Riou M.C.349,Caldas Rosa E.C.C.8ORCID,Soares de Lima Y.1011,dos Santos P.A.C.12,Alcaraz G.1ORCID,Guerra E.N.S.1,Castro L.C.13,de Oliveira S.F.1014,Pogue R.15,Berdal A.349,de Paula L.M.12,Mazzeu J.F.16,Cormier-Daire V.567,Acevedo A.C.1249

Affiliation:

1. Laboratory of Oral Histopathology, Faculty of Health Sciences, University of Brasília, Brasília, Brazil

2. Oral Care Center for Inherited Diseases, University Hospital of Brasília, Brasília, Brazil

3. Reference Center of Oral Rare Diseases O-Rares, Rothschild Hospital, Public Assistance—Paris Hospitals, Paris, France

4. Paris Cité University, Dental Faculty, Paris, France

5. Paris Cité University, INSERM UMR 1163 IMAGINE Institute, Paris, France

6. Reference Center for Skeletal Dysplasia, Service de Médecine Génomique des Maladies Rares, Necker Enfants Malades Hospital, Paris, France

7. Université Paris Cité, UFR de Médecine, Paris, France

8. Graduate Program of Health Sciences, Faculty of Health Sciences, University of Brasília, Brasília, Brazil

9. Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne University, UMRS 1138 Inserm, Molecular Oral Physiopathology, Paris, France

10. University of Brasília, Institute of Biological Sciences, Brasília, Brazil

11. Fundació de Recerca de l’Institut de Microcirurgia Ocular, Department of Genetics, Barcelona, Spain

12. Health Sciences University of Alagoas, Uncisal, Alagoas, Brazil

13. University Hospital of the University of Brasília, Pediatric Endocrinology, College of Health Sciences, University of Brasília, Brasília, Brazil

14. Department of Genetics and Morphology, Institute of Biological Sciences, University of Brasília, Brazil

15. Genomic Sciences and Biotechnology Program, Catholic University of Brasília, Brasília, Brazil

16. Laboratory of Clinical Genetics, Faculty of Medicine, University of Brasília, Brasília, Brazil

Abstract

Dentinogenesis imperfecta (DI) is the main orodental manifestation of osteogenesis imperfecta (OI) caused by COL1A1 or COL1A2 heterozygous pathogenic variants. Its prevalence varies according to the studied population. Here, we report the molecular analysis of 81 patients with OI followed at reference centers in Brazil and France presenting COL1A1 or COL1A2 variants. Patients were submitted to clinical and radiographic dental examinations to diagnose the presence of DI. In addition, a systematic literature search and a descriptive statistical analysis were performed to investigate OI/DI phenotype–genotype correlation in a worldwide sample. In our cohort, 50 patients had COL1A1 pathogenic variants, and 31 patients had COL1A2 variants. A total of 25 novel variants were identified. Overall, data from a total of 906 individuals with OI were assessed. Results show that DI was more frequent in severe and moderate OI cases. DI prevalence was also more often associated with COL1A2 (67.6%) than with COL1A1 variants (45.4%) because COL1A2 variants mainly lead to qualitative defects that predispose to DI more than quantitative defects. For the first time, 4 DI hotspots were identified. In addition, we showed that 1) glycine substitution by branched and charged amino acids in the α2(I) chain and 2) substitutions occurring in major ligand binding regions—MLRB2 in α1(I) and MLBR 3 in α2(I)—could significantly predict DI ( P < 0.05). The accumulated variant data analysis in this study provides a further basis for increasing our comprehension to better predict the occurrence and severity of DI and appropriate OI patient management.

Funder

COFECUB

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior

DPI - Decanato de Pesquisa e Inovação

Publisher

SAGE Publications

Subject

General Dentistry

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