New explanation for autosomal dominant high bone mass: Mutation of low-density lipoprotein receptor-related protein 6

Whyte, Michael P.; McAlister, William H.; Zhang, Fan; Bijanki, Vinieth N.; Nenninger, Angela; Gottesman, Gary S.; Lin, Elizabeth L.; Huskey, Margaret; Duan, Shenghui; Dahir, Kathryn; Mumm, Steven

doi:10.1016/j.bone.2019.05.003

Cited by 40 publications

(58 citation statements)

References 49 publications

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“…For example, the clinical features of RS and OMOD are similar which led to the hypothesis that all causative genes are involved in the WNT/PCP pathway which is previously shown to be important during limb development (Figure 2) (102). On the other hand, the influence of canonical WNT signaling on bone mass was highlighted by unraveling the underlying pathogenic mechanisms of disorders with a progressively increasing bone mass such as sclerosteosis, Van Buchem disease, and high bone mass phenotypes (osteosclerosis) (51,53,57,107,113). The genes causing these disorders, SOST, LRP4, LRP5, and LRP6, are all involved in the canonical WNT signaling pathway (Figure 3), and all mutations reported result in an increased canonical WNT signaling ( Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…However, recently, heterozygous mutations in the first β-propeller domain of LRP6 were identified in two families with HBM phenotype. The amino acids mutated in LRP6 are homologs to known LRP5 mutations (107). Although no functional studies were performed, it is highly likely that the mutations, similar to those reported for LRP5, disturb the binding of sclerostin and DKK1 and consequently result in increased WNT signaling activity and increased bone mass.…”

Section: Lrp6mentioning

confidence: 95%

“…However, LRP5/6 are lacking this motif (105). Mutations in three members of the LRP family, namely, LRP4, LRP5, and LRP6, are reported to result in rare skeletal disorders (51,106,107).…”

Section: Lrp Receptorsmentioning

confidence: 99%

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WNT Signaling and Bone: Lessons From Skeletal Dysplasias and Disorders

et al. 2020

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Skeletal dysplasias are a diverse group of heritable diseases affecting bone and cartilage growth. Throughout the years, the molecular defect underlying many of the diseases has been identified. These identifications led to novel insights in the mechanisms regulating bone and cartilage growth and homeostasis. One of the pathways that is clearly important during skeletal development and bone homeostasis is the Wingless and int-1 (WNT) signaling pathway. So far, three different WNT signaling pathways have been described, which are all activated by binding of the WNT ligands to the Frizzled (FZD) receptors. In this review, we discuss the skeletal disorders that are included in the latest nosology of skeletal disorders and that are caused by genetic defects involving the WNT signaling pathway. The number of skeletal disorders caused by defects in WNT signaling genes and the clinical phenotype associated with these disorders illustrate the importance of the WNT signaling pathway during skeletal development as well as later on in life to maintain bone mass. The knowledge gained through the identification of the genes underlying these monogenic conditions is used for the identification of novel therapeutic targets. For example, the genes underlying disorders with altered bone mass are all involved in the canonical WNT signaling pathway. Consequently, targeting this pathway is one of the major strategies to increase bone mass in patients with osteoporosis. In addition to increasing the insights in the pathways regulating skeletal development and bone homeostasis, knowledge of rare skeletal dysplasias can also be used to predict possible adverse effects of these novel drug targets. Therefore, this review gives an overview of the skeletal and extra-skeletal phenotype of the different skeletal disorders linked to the WNT signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Lrp6mentioning

confidence: 95%

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WNT Signaling and Bone: Lessons From Skeletal Dysplasias and Disorders

et al. 2020

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“…(3,4) Sclerostin, a key inhibitor of bone formation, was discovered through study of two rare syndromes of extreme high bone mass (HBM) due to mutations in SOST. (7,8) Together these sclerosing bone dysplasias are characterized by mandible enlargement with tori of the palate and mandible, bone overgrowth leading to nerve compression, a tendency to sink when swimming, and, importantly, resistance to fracture. Gain-of-function mutations in LRP5 and LRP6 can also cause extreme HBM.…”

Section: Introductionmentioning

confidence: 99%

“…Gain-of-function mutations in LRP5 and LRP6 can also cause extreme HBM. (7,8) Together these sclerosing bone dysplasias are characterized by mandible enlargement with tori of the palate and mandible, bone overgrowth leading to nerve compression, a tendency to sink when swimming, and, importantly, resistance to fracture. (5,7,9) These important gene discoveries validate the study of rare monogenic HBM as an approach to identify novel therapeutic targets for drug development toward osteoporosis treatments.…”

Section: Introductionmentioning

confidence: 99%

A Rare Mutation in SMAD9 Associated With High Bone Mass Identifies the SMAD-Dependent BMP Signaling Pathway as a Potential Anabolic Target for Osteoporosis

Gregson

Bergen

Leo

et al. 2019

Journal of Bone and Mineral Research

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Novel anabolic drug targets are needed to treat osteoporosis. Having established a large national cohort with unexplained high bone mass (HBM), we aimed to identify a novel monogenic cause of HBM and provide insight into a regulatory pathway potentially amenable to therapeutic intervention. We investigated a pedigree with unexplained HBM in whom previous sequencing had excluded known causes of monogenic HBM. Whole exome sequencing identified a rare (minor allele frequency 0.0023), highly evolutionarily conserved missense mutation in SMAD9 (c.65T>C, p.Leu22Pro) segregating with HBM in this autosomal dominant family. The same mutation was identified in another two unrelated individuals both with HBM. In silico protein modeling predicts the mutation severely disrupts the MH1 DNA‐binding domain of SMAD9. Affected individuals have bone mineral density (BMD) Z‐scores +3 to +5, mandible enlargement, a broad frame, torus palatinus/mandibularis, pes planus, increased shoe size, and a tendency to sink when swimming. Peripheral quantitative computed tomography (pQCT) measurement demonstrates increased trabecular volumetric BMD and increased cortical thickness conferring greater predicted bone strength; bone turnover markers are low/normal. Notably, fractures and nerve compression are not found. Both genome‐wide and gene‐based association testing involving estimated BMD measured at the heel in 362,924 white British subjects from the UK Biobank Study showed strong associations with SMAD9 (PGWAS = 6 × 10−16; PGENE = 8 × 10−17). Furthermore, we found Smad9 to be highly expressed in both murine cortical bone–derived osteocytes and skeletal elements of zebrafish larvae. Our findings support SMAD9 as a novel HBM gene and a potential novel osteoanabolic target for osteoporosis therapeutics. SMAD9 is thought to inhibit bone morphogenetic protein (BMP)‐dependent target gene transcription to reduce osteoblast activity. Thus, we hypothesize SMAD9 c.65T>C is a loss‐of‐function mutation reducing BMP inhibition. Lowering SMAD9 as a potential novel anabolic mechanism for osteoporosis therapeutics warrants further investigation. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

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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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New explanation for autosomal dominant high bone mass: Mutation of low-density lipoprotein receptor-related protein 6

Cited by 40 publications

References 49 publications

WNT Signaling and Bone: Lessons From Skeletal Dysplasias and Disorders

WNT Signaling and Bone: Lessons From Skeletal Dysplasias and Disorders

A Rare Mutation in SMAD9 Associated With High Bone Mass Identifies the SMAD-Dependent BMP Signaling Pathway as a Potential Anabolic Target for Osteoporosis

Wnt signalling in oral and maxillofacial diseases

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