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

Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research
Celia L GregsonEmma L Duncan

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 asympto...Continue Reading

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Citations

Sep 17, 2019·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Celia L GregsonEmma L Duncan
Jan 24, 2020·The Journal of Clinical Endocrinology and Metabolism·Hui PengStephen P Robertson
Oct 12, 2017·Calcified Tissue International·Sebastian ButscheidtRalf Oheim
Mar 3, 2020·Frontiers in Endocrinology·Robert Brommage, Claes Ohlsson
Oct 31, 2020·Cartilage·Achint UtrejaAlexander Robling
Jan 10, 2021·International Journal of Molecular Sciences·Núria Martínez-GilSusanna Balcells
Nov 17, 2020·Frontiers in Endocrinology·Celia L Gregson, Emma L Duncan
Feb 24, 2021·American Journal of Medical Genetics. Part a·Mamiko YamadaKenjiro Kosaki

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Methods Mentioned

BETA
chip
protein folding

Software Mentioned

ICM
Pro
Genalys
Stata
PMut
Illumina BeadStudio
Access
PolyPhen
Mutation Taster
SIFT

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