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.
Musculoskeletal Research Unit, School of Clinical Sciences, University of Bristol, Southmead Hospital, Bristol, UK.
Celia L
CL
Gregson
Human Genetics Group, University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia.
Lawrie
L
Wheeler
Musculoskeletal Research Unit, School of Clinical Sciences, University of Bristol, Southmead Hospital, Bristol, UK.
Sarah A
SA
Hardcastle
NIHR Oxford Musculoskeletal Biomedical Research Unit, Nuffield Orthopaedic Centre, Oxford, UK.
Louise H
LH
Appleton
Human Genetics Group, University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia.
Kathryn A
KA
Addison
Human Genetics Group, University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia.
Marieke
M
Brugmans
Human Genetics Group, University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia.
Graeme R
GR
Clark
MRC Human Nutrition Research Unit, Elsie Widdowson Laboratory, Cambridge, UK.
Kate A
KA
Ward
Mellanby Centre for Bone Research, Academic Unit of Bone Metabolism, University of Sheffield, Sheffield, UK.
Margaret
M
Paggiosi
Bone Research Unit, University Hospital Llandough, Cardiff and Vale University Health Board, Cardiff, UK.
Mike
M
Stone
James Paget University Hospital Foundation NHS Trust, Norfolk, UK.
Joegi
J
Thomas
Department of Medicine, University of Cambridge, Cambridge, UK.
Rohan
R
Agarwal
Department of Medicine, University of Cambridge, Cambridge, UK.
Kenneth E S
KE
Poole
Mellanby Centre for Bone Research, Academic Unit of Bone Metabolism, University of Sheffield, Sheffield, UK.
Eugene
E
McCloskey
Department of Medicine, Norwich Medical School, University of East Anglia, Norwich, UK.
William D
WD
Fraser
Structural Genomics Consortium, University of Oxford, Oxford, UK.
Eleanor
E
Williams
Structural Genomics Consortium, University of Oxford, Oxford, UK.
Alex N
AN
Bullock
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
George
G
Davey Smith
Human Genetics Group, University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia.
Matthew A
MA
Brown
Musculoskeletal Research Unit, School of Clinical Sciences, University of Bristol, Southmead Hospital, Bristol, UK.
Jon H
JH
Tobias
Musculoskeletal Research Unit, School of Clinical Sciences, University of Bristol, Southmead Hospital, Bristol, UK.|Royal Brisbane and Women's Hospital, Brisbane, Australia.
Emma L
EL
Duncan
D000328:Adult; D000368:Aged; D001842:Bone and Bones / Q000473:pathology*; D016022:Case-Control Studies; D015914:Estrogen Replacement Therapy; D005091:Exons / Q000235:genetics; D005260:Female; D056426:Genetic Loci; D006801:Humans; D008297:Male; D008593:Menopause; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D009929:Organ Size; D010641:Phenotype; D055815:Young Adult
ANABOLIC; LRP5; PROTEIN MODELING; SEQUENCING; SOST