Mutations in Known Monogenic High Bone Mass Loci Only Explain a Small Proportion of High Bone Mass Cases

Gregson, Celia L; Wheeler, Lawrie; Hardcastle, Sarah; Appleton, Louise; Addison, K.; Brugmans, Marieke; Clark, Graeme R.; Ward, Kate A; Paggiosi, Margaret; Stone, Mike; Thomas, Joegi; Agarwal, Rohan; Poole, Kenneth; McCloskey, Eugène; Fraser, William D.; Williams, Eleanor; Bullock, Alex N.; Smith, George Davey; Brown, Matthew A.; Tobias, Jonathan H; Duncan, Emma L.

doi:10.1002/jbmr.2706

Cited by 39 publications

(57 citation statements)

References 53 publications

(113 reference statements)

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“…1), (9) identified from our large UK HBM cohort (10) (Fig. 1), (9) identified from our large UK HBM cohort (10) (Fig.…”

Section: Leu22pro Variantmentioning

confidence: 87%

“…(46,47) We have previously estimated unexplained HBM to have a prevalence of 0.181% amongst a DXA-scanned adult population in the UK. (9) As rs111748421 has a reported MAF of 0.0028, this raises the possibility of incomplete penetrance, variable expressivity, genegene or gene-environment interaction with a currently unknown factor; it is also possible that rs111748421 might be in linkage disequilibrium (LD) with an intronic regulatory variant not captured by WES. S2 in File S1) were found to harbor the c.65T>C p.Leu22Pro SMAD9 variant (rs111748421), we would estimate prevalence of SMAD9 HBM as approximately 1 in 100,000 (1.46 × 10 −5 ), less common than LRP5 HBM.…”

Section: Discussionmentioning

confidence: 99%

“…In brief, DXA databases containing 335,115 DXA scans across 13 UK centers were searched; all scans explained by artefact or known causes of high BMD were excluded. (9) Anglo-Australasian Osteoporosis Genetics Consortium (AOGC) HBM and LBM cases The original AOGC extreme truncate population included 1128 Australian, 74 New Zealand, and 753 British women, aged 55 to 85 years, ≥5 years postmenopausal, with either HBM (age-and sex-adjusted TH BMD Z-scores +1.5 to +4.0, n = 1055) or low bone mass (LBM) (Z-scores −4.0 to −1.5, n = 900). A total of 533 unexplained HBM cases were invited to participate; 248 (47%) were recruited.…”

Section: Methodsmentioning

confidence: 99%

“…(5,6) SOST encodes Sclerostin, which binds to low-density lipoprotein receptor-related proteins 5 and 6 (LRP5 and LRP6) to prevent activation of canonical WNT signaling in bone, resulting in decreased bone formation. (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. (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.…”

Section: Introductionmentioning

confidence: 93%

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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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“…1), (9) identified from our large UK HBM cohort (10) (Fig. 1), (9) identified from our large UK HBM cohort (10) (Fig.…”

Section: Leu22pro Variantmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

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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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“…Extreme HBM is likely to be genetically determined with onset of elevated bone mass developing relatively early in life, likely before the onset of OA; the genetic basis of increased BMD in our HBM population is currently being investigated [42]. Potentially, the genetic influences governing BMD might also affect cartilage and OA risk.…”

Section: Discussionmentioning

confidence: 99%

High Bone Mass is associated with bone-forming features of osteoarthritis in non-weight bearing joints independent of body mass index

Gregson

Hardcastle

Murphy

et al. 2017

Bone

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ObjectivesHigh Bone Mass (HBM) is associated with (a) radiographic knee osteoarthritis (OA), partly mediated by increased BMI, and (b) pelvic enthesophytes and hip osteophytes, suggestive of a bone-forming phenotype. We aimed to establish whether HBM is associated with radiographic features of OA in non-weight-bearing (hand) joints, and whether such OA demonstrates a bone-forming phenotype.MethodsHBM cases (BMD Z-scores ≥ + 3.2) were compared with family controls. A blinded assessor graded all PA hand radiographs for: osteophytes (0–3), joint space narrowing (JSN) (0–3), subchondral sclerosis (0–1), at the index Distal Interphalangeal Joint (DIPJ) and 1st Carpometacarpal Joint (CMCJ), using an established atlas. Analyses used a random effects logistic regression model, adjusting a priori for age and gender. Mediating roles of BMI and bone turnover markers (BTMs) were explored by further adjustment.Results314 HBM cases (mean age 61.1 years, 74% female) and 183 controls (54.3 years, 46% female) were included. Osteophytes (grade ≥ 1) were more common in HBM (DIPJ: 67% vs. 45%, CMCJ: 69% vs. 50%), with adjusted OR [95% CI] 1.82 [1.11, 2.97], p = 0.017 and 1.89 [1.19, 3.01], p = 0.007 respectively; no differences were seen in JSN. Further adjustment for BMI failed to attenuate ORs for osteophytes in HBM cases vs. controls; DIPJ 1.72 [1.05, 2.83], p = 0.032, CMCJ 1.76 [1.00, 3.06], p = 0.049. Adjustment for BTMs (concentrations lower amongst HBM cases) did not attenuate ORs.ConclusionsHBM is positively associated with OA in non-weight-bearing joints, independent of BMI. HBM-associated OA is characterised by osteophytes, consistent with a bone-forming phenotype, rather than JSN reflecting cartilage loss. Systemic factors (e.g. genetic architecture) which govern HBM may also increase bone-forming OA risk.

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Fork‐shaped mandibular incisors as a novel phenotype of LRP5‐associated disorder

Yamada

Kubota

Uchida

et al. 2021

American J of Med Genetics Pt A

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The LRP5 gene encodes a Wnt signaling receptor to which Wnt binds directly. In humans, pathogenic monoallelic variants in LRP5 have been associated with increased bone density and exudative vitreoretinopathy. In mice, LRP5 plays a role in tooth development, including periodontal tissue stability and cementum formation. Here, we report a 14‐year‐old patient with a de novo non‐synonymous variant, p.(Val1245Met), in LRP5 who exhibited mildly reduced bone density and mild exudative vitreoretinopathy together with a previously unreported phenotype consisting of dental abnormalities that included fork‐like small incisors with short roots and an anterior open bite, molars with a single root, and severe taurodontism. In that exudative vitreoretinopathy has been reported to be associated with heterozygous loss‐of‐function variants of LRP5 and that our patient reported here with the p.(Val1245Met) variant had mild exudative vitreoretinopathy, the variant can be considered as an incomplete loss‐of‐function variant. Alternatively, the p.(Val1245Met) variant can be considered as exerting a dominant‐negative effect, as no patients with truncating LRP5 variants and exudative vitreoretinopathy have been reported to exhibit dental anomalies. The documentation of dental anomalies in the presently reported patient strongly supports the notion that LRP5 plays a critical role in odontogenesis in humans, similar to its role in mice.

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Mutations in Known Monogenic High Bone Mass Loci Only Explain a Small Proportion of High Bone Mass Cases

Cited by 39 publications

References 53 publications

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

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

High Bone Mass is associated with bone-forming features of osteoarthritis in non-weight bearing joints independent of body mass index

Fork‐shaped mandibular incisors as a novel phenotype of LRP5‐associated disorder

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