High bone mass from mutation of low-density lipoprotein receptor-related protein 6 (LRP6)

Brance, María Lorena; Brun, L.R.; Cóccaro, Nicolás; Aravena, Andrés; Duan, Shenghui; Mumm, Steven; Whyte, Michael P.

doi:10.1016/j.bone.2020.115550

Cited by 24 publications

(37 citation statements)

References 22 publications

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“…com/article/10.3390/jpm11111217/s1, Figure S1: Family 1 and a WNT10A p.(Arg113His) mutation; S1: Panel of 966 genes associated craniofacial development and anomalies; Table S2: Known LRP6 mutations associated with FTA. References [39][40][41][42][43][44][45][46][47] are cited in the supplementary materials.…”

Section: Supplementary Materialsmentioning

confidence: 99%

Synergistic Mutations of LRP6 and WNT10A in Familial Tooth Agenesis

Chu

Wang

Chou

et al. 2021

JPM

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Familial tooth agenesis (FTA), distinguished by developmental failure of selected teeth, is one of the most prevalent craniofacial anomalies in humans. Mutations in genes involved in WNT/β-catenin signaling, including AXIN2 WNT10A, WNT10B, LRP6, and KREMEN1, are known to cause FTA. However, mutational interactions among these genes have not been fully explored. In this study, we characterized four FTA kindreds with LRP6 pathogenic mutations: p.(Gln1252*), p.(Met168Arg), p.(Ala754Pro), and p.(Asn1075Ser). The three missense mutations were predicted to cause structural destabilization of the LRP6 protein. Two probands carrying both an LRP6 mutant allele and a WNT10A variant exhibited more severe phenotypes, suggesting mutational synergism or digenic inheritance. Biallelic LRP6 mutations in a patient with many missing teeth further supported the dose-dependence of LRP6-associated FTA. Analysis of 21 FTA cases with 15 different LRP6 loss-of-function mutations revealed high heterogeneity of disease severity and a distinctive pattern of missing teeth, with maxillary canines being frequently affected. We hypothesized that various combinations of sequence variants in WNT-related genes can modulate WNT signaling activities during tooth development and cause a wide spectrum of tooth agenesis severity, which highlights the importance of exome/genome analysis for the genetic diagnosis of FTA in this era of precision medicine.

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Section: Supplementary Materialsmentioning

confidence: 99%

Synergistic Mutations of LRP6 and WNT10A in Familial Tooth Agenesis

Chu

Wang

Chou

et al. 2021

JPM

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“…As shown in Figure 6, studies found that mutations of the receptor protein of Wnt signalling were related to jaw sclerosis. Some reports showed that LPR5/6 mutations could lead to increased bone mass, which manifested as LPR5/6 mutations that may account for sclerotic thickening of the skull, orbital roof thickening dense petrous bone, and thickened mandibular cortex (Brance et al, 2020; Costantini et al, 2017; Whyte et al, 2019).…”

Section: Wnt and Other Diseasesmentioning

confidence: 99%

Wnt signalling in oral and maxillofacial diseases

Zhang

Pan

Chen

et al. 2021

Cell Biology International

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Wnts include more than 19 types of secreted glycoproteins that are involved in a wide range of pathological processes in oral and maxillofacial diseases. The transmission of Wnt signalling from the extracellular matrix into the nucleus includes canonical pathways and noncanonical pathways, which play an important role in tooth development, alveolar bone regeneration, and related diseases. In recent years, with the in‐depth study of Wnt signalling in oral and maxillofacial‐related diseases, many new conclusions and perspectives have been reached, and there are also some controversies. This article aims to summarise the roles of Wnt signalling in various oral diseases, including periodontitis, dental pulp disease, jaw disease, cleft palate, and abnormal tooth development, to provide researchers with a better and more comprehensive understanding of Wnts in oral and maxillofacial diseases.

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“…Loss-of-function mutations of LRP5 cause osteoporosis-pseudoglioma syndrome (OPPG; OMIM: 259,770) characterized by severe osteoporosis [17] and gain-of-function mutations led to high-bone-mass (HBM) phenotypes [18,19]. In addition, it was recently reported that gain-of-function mutations of LRP6 also exhibit HBM phenotypes [20,21]. These results clearly demonstrate the critical role of canonical Wnt-LRP5/6 signaling pathways to regulate bone formation.…”

Section: Sclerostin and Canonical Wnt Signalingmentioning

confidence: 99%

Sclerostin: from bench to bedside

Tanaka

Matsumoto

2020

J Bone Miner Metab

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Skeletal integrity is maintained by a meticulous balance between bone resorption and bone formation, and recent studies have revealed the essential role of canonical Wnt signaling pathways in maintaining skeletal homeostasis. The SOST gene, which encodes sclerostin, a member of Dan family glycoproteins, was originally identified as the gene responsible for two sclerosing bone dysplasias, sclerosteosis and van Buchem disease. Sclerostin is highly expressed by osteocytes, negatively regulates canonical Wnt signaling pathways by binding to low-density lipoprotein receptor-related protein (LRP) 5/6, and suppresses osteoblast differentiation and/or function. Romosozumab, a specific anti-sclerostin antibody, inhibits sclerostin-LRP5/6 interactions and indirectly activates canonical Wnt signaling pathways and bone formation. This review focuses on the mechanism of action of sclerostin and summarizes clinical studies that demonstrated the efficacy of romosozumab to increase bone mineral density and reduce osteoporotic fractures, as well as its cardiovascular safety.

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High bone mass from mutation of low-density lipoprotein receptor-related protein 6 (LRP6)

Cited by 24 publications

References 22 publications

Synergistic Mutations of LRP6 and WNT10A in Familial Tooth Agenesis

Synergistic Mutations of LRP6 and WNT10A in Familial Tooth Agenesis

Wnt signalling in oral and maxillofacial diseases

Sclerostin: from bench to bedside

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