Clinical Phenotype and Relevance of LRP5 and LRP6 Variants in Patients With Early-Onset Osteoporosis (EOOP).
BONE REMODELING
LRP5
LRP6
OSTEOPOROSIS
WNT SIGNALING
Journal
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
ISSN: 1523-4681
Titre abrégé: J Bone Miner Res
Pays: United States
ID NLM: 8610640
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
03
07
2020
revised:
08
10
2020
accepted:
13
10
2020
pubmed:
30
10
2020
medline:
10
8
2021
entrez:
29
10
2020
Statut:
ppublish
Résumé
Reduced bone mineral density (BMD; ie, Z-score ≤-2.0) occurring at a young age (ie, premenopausal women and men <50 years) in the absence of secondary osteoporosis is considered early-onset osteoporosis (EOOP). Mutations affecting the WNT signaling pathway are of special interest because of their key role in bone mass regulation. Here, we analyzed the effects of relevant LRP5 and LRP6 variants on the clinical phenotype, bone turnover, BMD, and bone microarchitecture. After exclusion of secondary osteoporosis, EOOP patients (n = 372) were genotyped by gene panel sequencing, and segregation analysis of variants in LRP5/LRP6 was performed. The clinical assessment included the evaluation of bone turnover parameters, BMD by dual-energy X-ray absorptiometry, and microarchitecture via high-resolution peripheral quantitative computed tomography (HR-pQCT). In 50 individuals (31 EOOP index patients, 19 family members), relevant variants affecting LRP5 or LRP6 were detected (42 LRP5 and 8 LRP6 variants), including 10 novel variants. Seventeen variants were classified as disease causing, 14 were variants of unknown significance, and 19 were BMD-associated single-nucleotide polymorphisms (SNPs). One patient harbored compound heterozygous LRP5 mutations causing osteoporosis-pseudoglioma syndrome. Fractures were reported in 37 of 50 individuals, consisting of vertebral (18 of 50) and peripheral (29 of 50) fractures. Low bone formation was revealed in all individuals. A Z-score ≤-2.0 was detected in 31 of 50 individuals, and values at the spine were significantly lower than those at the hip (-2.1 ± 1.3 versus -1.6 ± 0.8; p = .003). HR-pQCT analysis (n = 34) showed impaired microarchitecture in trabecular and cortical compartments. Significant differences regarding the clinical phenotype were detectable between index patients and family members but not between different variant classes. Relevant variants in LRP5 and LRP6 contribute to EOOP in a substantial number of individuals, leading to a high number of fractures, low bone formation, reduced Z-scores, and impaired microarchitecture. This detailed skeletal characterization improves the interpretation of known and novel LRP5 and LRP6 variants. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Substances chimiques
LRP5 protein, human
0
LRP6 protein, human
0
Low Density Lipoprotein Receptor-Related Protein-5
0
Low Density Lipoprotein Receptor-Related Protein-6
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
271-282Informations de copyright
© 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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