Early-Onset Osteoporosis: Molecular Analysis in Large Cohort and Focus on the PLS3 Gene

Maxence Mancini¹, Roland Chapurlat², Bertrand Isidor³, Marine Desjonqueres⁴, Guillaume Couture⁵, Pascal Guggenbuhl⁶, Régis Coutant⁷, Salima El Chehadeh⁸, Mélanie Fradin⁹, Aline Frazier¹⁰, Alice Goldenberg¹¹, Pascaline Guillot¹², Eugénie Koumakis¹³, Nadia Mehsen-Cêtre¹⁴, Massimiliano Rossi¹⁵, Élise Schaefer⁸, Sabine Sigaudy¹⁶, Valérie Porquet-Bordes¹⁷, Élisabeth Fontanges², Pauline Letard¹⁸, Thomas Edouard¹⁷, Rose-Marie Javier¹⁹, Martine Cohen-Solal¹⁰, Thomas Funck-Brentano¹⁰, Corinne Collet²⁰

Affiliations

¹ Biochemistry and Molecular Genetics Department, Lariboisière Hospital, AP-HP, Paris, France.
² Rheumatology and Bone Pathology Department, Inserm UMR 1033, Université de Lyon, Edouard Herriot Hospital, HCL, Lyon, France.
³ Medical Genetics Department, CHU de Nantes, Hôtel Dieu Hospital, Nantes, France.
⁴ Nephrology - Rheumatology - Dermatology Paediatric Department, Edouard Herriot Hospital, HCL, Lyon, France.
⁵ Endocrine, Bone Diseases and Genetics Unit, Rheumatology Department, Reference Centre for Rare Diseases of Calcium and Phosphate Metabolism, ERN BOND, OSCAR Network, University Hospital, RESTORE, INSERM U1301, Toulouse, France.
⁶ Rheumatology Department, CHU Rennes, Sud Hospital, Rennes, France.
⁷ Department of Paediatrics and Endocrinology, CHU d'Angers, Angers, France.
⁸ Medical Genetics Department, Institut de Génétique Médicale d'alsace, CHU de Strasbourg, Strasbourg, France.
⁹ Clinical Genetics Department, CHU Rennes, Sud Hospital, Rennes, France.
¹⁰ Rheumatology Department, Inserm 1132, Univsersité Paris-Cité, Lariboisière Hospital, AP-HP, Paris, France.
¹¹ Medical Genetics Department, Charles- Nicolle Hospital, CHU de Rouen, Rouen, France.
¹² Rheumatology Department, CHU de Nantes, Hôpital Hôtel Dieu, Nantes, France.
¹³ Rheumatology Department, Cochin Hospital, AP-HP, Paris, France.
¹⁴ Rheumatology Department, CHU Pellegrin, Bordeaux, France.
¹⁵ Medical Genetics Department, Edouard Herriot Hospital, HCL, Lyon, France.
¹⁶ Medical Genetics Department, CHU de Marseille, Timone Hospital, Marseille, France.
¹⁷ Endocrine, Bone Diseases and Genetics Unit, Reference Centre for Rare Diseases of Calcium and Phosphate Metabolism, ERN BOND, OSCAR Network, Paediatric Research Unit, Children's Hospital, Toulouse University Hospital, RESTORE, INSERM U1301, Toulouse, France.
¹⁸ Medical Genetics Department, CHU de Poitiers, Poitiers, France.
¹⁹ Rheumatology Department, CHU de Strasbourg, Hautepierre Hospital, Strasbourg, France.
²⁰ Rare Disease Genomic Medicine Department, CHU Necker-Enfants Malades, INSERM UMR1163, Institut Imagine, Université Paris-Cité, Paris, France. corinne.collet@aphp.fr.

PMID: 39316135
DOI: 10.1007/s00223-024-01288-z

Early-Onset Osteoporosis: Molecular Analysis in Large Cohort and Focus on the PLS3 Gene

Maxence Mancini et al. Calcif Tissue Int. 2024 Nov.

. 2024 Nov;115(5):591-598.

doi: 10.1007/s00223-024-01288-z. Epub 2024 Sep 24.

Authors

Affiliations

¹ Biochemistry and Molecular Genetics Department, Lariboisière Hospital, AP-HP, Paris, France.
² Rheumatology and Bone Pathology Department, Inserm UMR 1033, Université de Lyon, Edouard Herriot Hospital, HCL, Lyon, France.
³ Medical Genetics Department, CHU de Nantes, Hôtel Dieu Hospital, Nantes, France.
⁴ Nephrology - Rheumatology - Dermatology Paediatric Department, Edouard Herriot Hospital, HCL, Lyon, France.
⁵ Endocrine, Bone Diseases and Genetics Unit, Rheumatology Department, Reference Centre for Rare Diseases of Calcium and Phosphate Metabolism, ERN BOND, OSCAR Network, University Hospital, RESTORE, INSERM U1301, Toulouse, France.
⁶ Rheumatology Department, CHU Rennes, Sud Hospital, Rennes, France.
⁷ Department of Paediatrics and Endocrinology, CHU d'Angers, Angers, France.
⁸ Medical Genetics Department, Institut de Génétique Médicale d'alsace, CHU de Strasbourg, Strasbourg, France.
⁹ Clinical Genetics Department, CHU Rennes, Sud Hospital, Rennes, France.
¹⁰ Rheumatology Department, Inserm 1132, Univsersité Paris-Cité, Lariboisière Hospital, AP-HP, Paris, France.
¹¹ Medical Genetics Department, Charles- Nicolle Hospital, CHU de Rouen, Rouen, France.
¹² Rheumatology Department, CHU de Nantes, Hôpital Hôtel Dieu, Nantes, France.
¹³ Rheumatology Department, Cochin Hospital, AP-HP, Paris, France.
¹⁴ Rheumatology Department, CHU Pellegrin, Bordeaux, France.
¹⁵ Medical Genetics Department, Edouard Herriot Hospital, HCL, Lyon, France.
¹⁶ Medical Genetics Department, CHU de Marseille, Timone Hospital, Marseille, France.
¹⁷ Endocrine, Bone Diseases and Genetics Unit, Reference Centre for Rare Diseases of Calcium and Phosphate Metabolism, ERN BOND, OSCAR Network, Paediatric Research Unit, Children's Hospital, Toulouse University Hospital, RESTORE, INSERM U1301, Toulouse, France.
¹⁸ Medical Genetics Department, CHU de Poitiers, Poitiers, France.
¹⁹ Rheumatology Department, CHU de Strasbourg, Hautepierre Hospital, Strasbourg, France.
²⁰ Rare Disease Genomic Medicine Department, CHU Necker-Enfants Malades, INSERM UMR1163, Institut Imagine, Université Paris-Cité, Paris, France. corinne.collet@aphp.fr.

PMID: 39316135
DOI: 10.1007/s00223-024-01288-z

Abstract

Osteoporosis is a skeletal disorder characterized by abnormal bone microarchitecture and low bone mineral density (BMD), responsible for an increased risk of fractures and skeletal fragility. It is a common pathology of the aging population. However, when osteoporosis occurs in children or young adults, it strongly suggests an underlying genetic etiology. Over the past two decades, several genes have been identified as responsible for this particular kind of considered monogenic early-onset osteoporosis (EOOP) or juvenile osteoporosis, the main ones being COL1A1, COL1A2, LRP5, LRP6, WNT1, and more recently PLS3. In this study, the objective was to characterize a large cohort of patients diagnosed with primary osteoporosis and to establish its diagnosis yield. The study included 577 patients diagnosed with primary osteoporosis and its diagnosis yield was established. To this end, next-generation sequencing (NGS) of a panel of 21 genes known to play a role in bone fragility was carried out. A genetic etiology was explained in about 18% of cases, while the others remain unexplained. The most frequently identified gene associated with EOOP is LRP5, which was responsible for 8.2% of the positive results (47 patients). As unexpected, 17 patients (2.9%) had a variant in PLS3 which encodes plastin 3. Alterations of PLS3 are associated with dominant X-linked osteoporosis, an extremely rare disease. Given the rarity of this disease, we focused on it. It was observed that males were more affected than females, but it is noteworthy that three females with a particularly severe phenotype were identified. Of these three, two had a variant in an additional gene involved in EOP, illustrating the probable existence of digenism. We significantly increase the number of variants potentially associated with EOOP, especially in PLS3. The results of our study demonstrate that molecular analysis in EOOP is beneficial and useful.

Keywords: LRP5; PLS3; Digenism; Early-onset osteoporosis.

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References

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Early-Onset Osteoporosis: Molecular Analysis in Large Cohort and Focus on the PLS3 Gene

Affiliations

Early-Onset Osteoporosis: Molecular Analysis in Large Cohort and Focus on the PLS3 Gene

Authors

Affiliations

Abstract

References

MeSH terms

Substances

Supplementary concepts

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

Research Materials

Miscellaneous