Gregson Celia L, Wheeler Lawrie, Hardcastle Sarah A, Appleton Louise H, Addison Kathryn A, Brugmans Marieke, Clark Graeme R, Ward Kate A, Paggiosi Margaret, Stone Mike, Thomas Joegi, Agarwal Rohan, Poole Kenneth E S, McCloskey Eugene, Fraser William D, Williams Eleanor, Bullock Alex N, Davey Smith George, Brown Matthew A, Tobias Jon H, Duncan Emma L
Musculoskeletal Research Unit, School of Clinical Sciences, University of Bristol, Southmead Hospital, Bristol, UK.
Human Genetics Group, University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia.
J Bone Miner Res. 2016 Mar;31(3):640-9. doi: 10.1002/jbmr.2706. Epub 2015 Oct 6.
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.
高骨量（HBM）可能是偶然的临床发现；然而，单基因HBM疾病（如LRP5或SOST突变）很少见。我们旨在确定已知HBM基因中的突变在多大程度上可以解释HBM。通过回顾来自英国13个中心的335115次双能X线吸收法（DXA）扫描，共识别出258例无亲缘关系的HBM病例。对这些病例进行临床评估，并对已知的合成代谢HBM基因座进行测序：LRP5（第2、3、4外显子）、LRP4（第25、26外显子）、SOST（第1、2外显子以及范布赫姆病[VBD]52 kb内含子缺失3'）。对家庭成员进行评估，以确定所识别的变异与HBM的分离情况。为所识别的变异构建三维蛋白质模型。识别出两个新的LRP5 HBM错义突变（[c.518C>T；p.Thr173Met]，[c.796C>T；p.Arg266Cys]），以及三个先前报道的LRP5错义突变（[c.593A>G；p.Asn198Ser]，[c.724G>A；p.Ala242Thr]，[c.266A>G；p.Gln89Arg]），这些突变与来自7个家庭的11名成年人的HBM相关。与非LRP5 HBM个体和对照组相比，LRP5 HBM个体（患病率约为5/100000）表现出骨骼发育异常的可变表型，高分辨率外周定量CT显示小梁骨密度和皮质厚度增加，DXA显示臀部脂肪量增加。一名大多无症状的女性携带一个新的杂合性SOST无义突变（c.530C>A；p.Ser177X），预计该突变会使硬化蛋白过早截断。蛋白质建模表明，LRP5 - HBM表型的严重程度与蛋白质破坏程度以及对SOST - LRP5结合的后续影响相对应。我们预测p.Asn198Ser和p.Ala242Thr直接破坏SOST结合；两者均对应严重的HBM表型（骨密度Z值为+3.1至+12.2，无法漂浮）。p.Arg266Cys、p.Thr173Met和p.Gln89Arg预测的破坏性较小的结构改变与不太严重的表型相关（Z值为+2.4至+6.2，能够漂浮）。总之，尽管已知HBM基因座中的突变可能无症状，但它们仅占HBM个体的极小比例（约3%），这表明绝大多数HBM个体是由未知的单基因原因或多基因遗传所解释。
