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Mutations in known monogenic high bone mass loci only explain a small proportion of high bone mass cases

Mutations in known monogenic high bone mass loci only explain a small proportion of high bone mass cases
Mutations in known monogenic high bone mass loci only explain a small proportion of high bone mass cases
High bone mass (HBM) can be an incidental clinical finding; however, monogenic HBM disorders (eg, LRP5 or SOST mutations) are rare. We aimed to determine to what extent HBM is explained by mutations in known HBM genes. A total of 258 unrelated HBM cases were identified from a review of 335,115 DXA scans from 13 UK centers. Cases were assessed clinically and underwent sequencing of known anabolic HBM loci: LRP5 (exons 2, 3, 4), LRP4 (exons 25, 26), SOST (exons 1, 2, and the van Buchem's disease [VBD] 52-kb intronic deletion 3?). Family members were assessed for HBM segregation with identified variants. Three-dimensional protein models were constructed for identified variants. Two novel missense LRP5 HBM mutations ([c.518C>T; p.Thr173Met], [c.796C>T; p.Arg266Cys]) were identified, plus three previously reported missense LRP5 mutations ([c.593A>G; p.Asn198Ser], [c.724G>A; p.Ala242Thr], [c.266A>G; p.Gln89Arg]), associated with HBM in 11 adults from seven families. Individuals with LRP5 HBM (?prevalence 5/100,000) displayed a variable phenotype of skeletal dysplasia with increased trabecular BMD and cortical thickness on HRpQCT, and gynoid fat mass accumulation on DXA, compared with both non-LRP5 HBM and controls. One mostly asymptomatic woman carried a novel heterozygous nonsense SOST mutation (c.530C>A; p.Ser177X) predicted to prematurely truncate sclerostin. Protein modeling suggests the severity of the LRP5-HBM phenotype corresponds to the degree of protein disruption and the consequent effect on SOST-LRP5 binding. We predict p.Asn198Ser and p.Ala242Thr directly disrupt SOST binding; both correspond to severe HBM phenotypes (BMD Z-scores +3.1 to +12.2, inability to float). Less disruptive structural alterations predicted from p.Arg266Cys, p.Thr173Met, and p.Gln89Arg were associated with less severe phenotypes (Z-scores +2.4 to +6.2, ability to float). In conclusion, although mutations in known HBM loci may be asymptomatic, they only account for a very small proportion (?3%) of HBM individuals, suggesting the great majority are explained by either unknown monogenic causes or polygenic inheritance. © 2015 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).
0884-0431
640-649
Gregson, C.L.
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Wheeler, L.
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Hardcastle, S.A.
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Appleton, L.H.
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Addison, K.A.
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Brugmans, M.
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Clark, G.R.
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Ward, K.
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Paggiosi, M.
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Stone, M.
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Thomas, J.
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Agarwal, R.
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Poole, K.E.
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McCloskey, E.
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Fraser, W.D.
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Williams, E.
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Bullock, A.N.
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Davey Smith, G.
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Brown, M.A.
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Tobias, J.H.
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Duncan, E.L.
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Gregson, C.L.
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Wheeler, L.
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Hardcastle, S.A.
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Appleton, L.H.
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Addison, K.A.
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Brugmans, M.
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Clark, G.R.
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Ward, K.
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Paggiosi, M.
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Stone, M.
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Thomas, J.
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Agarwal, R.
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Poole, K.E.
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McCloskey, E.
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Fraser, W.D.
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Williams, E.
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Bullock, A.N.
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Davey Smith, G.
cb29a020-3ad3-4bcd-95dc-a1a43d4fe26f
Brown, M.A.
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Tobias, J.H.
de2ae2cb-8547-475a-98e0-9d5169b8deb7
Duncan, E.L.
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Gregson, C.L., Wheeler, L., Hardcastle, S.A., Appleton, L.H., Addison, K.A., Brugmans, M., Clark, G.R., Ward, K., Paggiosi, M., Stone, M., Thomas, J., Agarwal, R., Poole, K.E., McCloskey, E., Fraser, W.D., Williams, E., Bullock, A.N., Davey Smith, G., Brown, M.A., Tobias, J.H. and Duncan, E.L. (2016) Mutations in known monogenic high bone mass loci only explain a small proportion of high bone mass cases. Journal of Bone and Mineral Research, 31 (3), 640-649. (doi:10.1002/jbmr.2706). (PMID:26348019)

Record type: Article

Abstract

High bone mass (HBM) can be an incidental clinical finding; however, monogenic HBM disorders (eg, LRP5 or SOST mutations) are rare. We aimed to determine to what extent HBM is explained by mutations in known HBM genes. A total of 258 unrelated HBM cases were identified from a review of 335,115 DXA scans from 13 UK centers. Cases were assessed clinically and underwent sequencing of known anabolic HBM loci: LRP5 (exons 2, 3, 4), LRP4 (exons 25, 26), SOST (exons 1, 2, and the van Buchem's disease [VBD] 52-kb intronic deletion 3?). Family members were assessed for HBM segregation with identified variants. Three-dimensional protein models were constructed for identified variants. Two novel missense LRP5 HBM mutations ([c.518C>T; p.Thr173Met], [c.796C>T; p.Arg266Cys]) were identified, plus three previously reported missense LRP5 mutations ([c.593A>G; p.Asn198Ser], [c.724G>A; p.Ala242Thr], [c.266A>G; p.Gln89Arg]), associated with HBM in 11 adults from seven families. Individuals with LRP5 HBM (?prevalence 5/100,000) displayed a variable phenotype of skeletal dysplasia with increased trabecular BMD and cortical thickness on HRpQCT, and gynoid fat mass accumulation on DXA, compared with both non-LRP5 HBM and controls. One mostly asymptomatic woman carried a novel heterozygous nonsense SOST mutation (c.530C>A; p.Ser177X) predicted to prematurely truncate sclerostin. Protein modeling suggests the severity of the LRP5-HBM phenotype corresponds to the degree of protein disruption and the consequent effect on SOST-LRP5 binding. We predict p.Asn198Ser and p.Ala242Thr directly disrupt SOST binding; both correspond to severe HBM phenotypes (BMD Z-scores +3.1 to +12.2, inability to float). Less disruptive structural alterations predicted from p.Arg266Cys, p.Thr173Met, and p.Gln89Arg were associated with less severe phenotypes (Z-scores +2.4 to +6.2, ability to float). In conclusion, although mutations in known HBM loci may be asymptomatic, they only account for a very small proportion (?3%) of HBM individuals, suggesting the great majority are explained by either unknown monogenic causes or polygenic inheritance. © 2015 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).

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Accepted/In Press date: 4 September 2015
e-pub ahead of print date: 6 October 2015
Published date: March 2016
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 397414
URI: http://eprints.soton.ac.uk/id/eprint/397414
ISSN: 0884-0431
PURE UUID: 63599fb5-e7e4-4f43-a10c-0a27722d3efb
ORCID for K. Ward: ORCID iD orcid.org/0000-0001-7034-6750

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Date deposited: 29 Jun 2016 15:26
Last modified: 17 Dec 2019 01:33

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Contributors

Author: C.L. Gregson
Author: L. Wheeler
Author: S.A. Hardcastle
Author: L.H. Appleton
Author: K.A. Addison
Author: M. Brugmans
Author: G.R. Clark
Author: K. Ward ORCID iD
Author: M. Paggiosi
Author: M. Stone
Author: J. Thomas
Author: R. Agarwal
Author: K.E. Poole
Author: E. McCloskey
Author: W.D. Fraser
Author: E. Williams
Author: A.N. Bullock
Author: G. Davey Smith
Author: M.A. Brown
Author: J.H. Tobias
Author: E.L. Duncan

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