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 ( approximately 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 ( approximately 3%) of HBM individuals, suggesting the great majority are explained by either unknown monogenic causes or polygenic inheritance.

Zaburoni HIV case: The law can sometimes be an ass, but not in this case

Lana Nowakowski's opinion piece on the High Court decision in the Zaburoni HIV case attacks "Queensland's absurd necessity to prove intention on transmission" and argues that "changes to the law are long overdue". Both claims are wrong...

(Failed) voluntary euthanasia law reform in Australia: Two decades of trends, models and politics

Within Australia, there have been many attempts to pass voluntary euthanasia (VE) or physician-assisted suicide (PAS) legislation. From 16 June 1993 until the date of writing, 51 Bills have been introduced into Australian parliaments dealing with legalising VE or PAS. Despite these numerous attempts, the only successful Bill was the Rights of the Terminally Ill Act 1995 (NT), which was enacted in the Northern Territory, but a short time later overturned by the controversial Euthanasia Laws Act 1997 (Cth). Yet, in stark contrast to the significant political opposition, for decades Australian public opinion has overwhelmingly supported law reform legalising VE or PAS. While there is ongoing debate in Australia, both through public discourse and scholarly publications, about the merits and dangers of reform in this field, there has been remarkably little analysis of the numerous legislative attempts to reform the law, and the context in which those reform attempts occurred. The aim of this article is to better understand the reform landscape in Australia over the past two decades. The information provided in this article will better equip Australians, both politicians and the general public, to have a more nuanced understanding of the political context in which the euthanasia debate has been and is occurring. It will also facilitate a more informed debate in the future.