Genetic determinants contribute to osteoporosis and enhance the risk of fracture. Genomewide association studies of unselected population‐based individuals or families have identified polymorphisms in several genes related to low bone density, but not in osteoporotic patients with Z‐score < −2.0 SD with fragility fracture(s). The aim of this study was to determine the causal genes of idiopathic osteoporosis in the adulthood. Also, we used next‐generation sequencing of candidate genes in a cohort of 123 young or middle‐aged adults with idiopathic osteoporosis. All patients were included if they had a low bone mineral density (Z‐score < −2 SD), a diagnosis before age 55 years (mean ± SD, 48.4 ± 10.6 years; mean ± SD age at first fracture, 30.4 ± 17.4 years) and fracture or not. We found that 11 patients carried rare or novel variants in COL1A2 (n = 4), PLS3 (n = 2), WNT1 (n = 4), or DKK1 (n = 1). We showed a high prevalence of pathogenic variants in LRP5: 22 patients (17.8%) had the p.Val667Met variant, including three at the homozygous level and 16 (13%) carrying a novel or very rare variant. Functional analysis revealed that the LRP5 missense variants resulted in reduced luciferase activity, which indicates reduced activation of canonical WNT signaling. The clinical phenotype of patients carrying causal gene variants was indistinguishable. In conclusion, molecular screening of young osteoporotic adults revealed several variants and could be useful to characterize susceptibility genes for personalizing treatment, in particular for the new anabolic drugs.© 2017 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.
Whole-cell biosensors based on reporter genes allow detection of toxic metals in water with high selectivity and sensitivity under laboratory conditions; nevertheless, their transfer to a commercial inline water analyzer requires specific adaptation and optimization to field conditions as well as economical considerations. We focused here on both the influence of the bacterial host and the choice of the reporter gene by following the responses of global toxicity biosensors based on constitutive bacterial promoters as well as arsenite biosensors based on the arsenite-inducible P promoter. We observed important variations of the bioluminescence emission levels in five different Escherichia coli strains harboring two different lux-based biosensors, suggesting that the best host strain has to be empirically selected for each new biosensor under construction. We also investigated the bioluminescence reporter gene system transferred into Deinococcus deserti, an environmental, desiccation- and radiation-tolerant bacterium that would reduce the manufacturing costs of bacterial biosensors for commercial water analyzers and open the field of biodetection in radioactive environments. We thus successfully obtained a cell survival biosensor and a metal biosensor able to detect a concentration as low as 100 nM of arsenite in D. deserti. We demonstrated that the arsenite biosensor resisted desiccation and remained functional after 7 days stored in air-dried D. deserti cells. We also report here the use of a new near-infrared (NIR) fluorescent reporter candidate, a bacteriophytochrome from the magnetotactic bacterium Magnetospirillum magneticum AMB-1, which showed a NIR fluorescent signal that remained optimal despite increasing sample turbidity, while in similar conditions, a drastic loss of the lux-based biosensors signal was observed.
Background: Cherubism is a rare autosomal dominant genetic condition caused by mutations in the SH3BP2 gene. This disease is characterized by osteolysis of the jaws, with the bone replaced by soft tissue rich in fibroblasts and multinuclear giant cells. SH3BP2 is a ubiquitous adaptor protein yet the consequences of SH3BP2 mutation have so far been described as impacting only face. Cherubism mouse models have been generated and unlike human patients, the knock-in mice exhibit systemic bone loss together with a systemic inflammation. Case presentation: In light of these observations, we decided to search for a systemic cherubism phenotype in a 6-year-old girl with an aggressive cherubism. We report here the first case of cherubism with systemic manifestations. Bone densitometry showed low overall bone density (total body Z-score = − 4.6 SD). Several markers of bone remodelling (CTx, BALP, P1NP) as well as inflammation (TNFα and IL-1) were elevated. A causative second-site mutation in other genes known to influence bone density was ruled out by sequencing a panel of such genes. Conclusions: If this systemic skeletal cherubism phenotype should be confirmed, it would simplify the treatment of severe cherubism patients and allay reservations about applying a systemic treatment such as those recently published (tacrolimus or imatinib) to a disease heretofore believed to be localised to the jaws.
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Monogenic early-onset osteoporosis (EOOP) is a rare disease defined by low bone mineral density (BMD) that results in increased risk of fracture in children and young adults. Although several causative genes have been identified, some of the EOOP causation remains unresolved. Whole-exome sequencing revealed a de novo heterozygous loss-of-function mutation in WNT11 (NM_004626.2:c.677_678dup p.Leu227Glyfs*22) in a 4-year-old boy with low BMD and fractures. We identified two heterozygous WNT11 missense variants (NM_004626.2:c.217G > A p.Ala73Thr) and (NM_004626.2:c.865G > A p.Val289Met) in a 51-year-old woman and in a 61-year-old woman respectively, both with bone fragility. U2OS cells with heterozygous WNT11 mutation (NM_004626.2:c.690_721delfs*40) generated by CRISPR-Cas9 showed reduced cell proliferation (30%) and osteoblast differentiation (80%) as compared with wild-type U2OS cells. The expression of genes in the Wnt canonical and non-canonical pathways was inhibited in these mutant cells, but recombinant WNT11 treatment rescued the expression of Wnt pathway target genes. Furthermore, the expression of RSPO2, a WNT11 target involved in bone cell differentiation, and its receptor LGR5, was decreased in WNT11 mutant cells. Treatment with WNT5A and WNT11 recombinant proteins reversed LGR5 expression, but WNT3A recombinant protein treatment had no effect on LGR5 expression in mutant cells. Moreover, treatment with recombinant RSPO2 but not WNT11 or WNT3A activated the canonical pathway in mutant cells. In conclusion, we have identified WNT11 as a new gene responsible for EOOP, with loss-of-function variant inhibiting bone formation via Wnt canonical and non-canonical pathways. WNT11 may activate Wnt signaling by inducing the RSPO2–LGR5 complex via the non-canonical Wnt pathway.
BackgroundEarly-onset or juvenile gout (EOG) without hypoxanthine-guanine phosphoribosyltransferase enzyme deficiency (HPRT, OMIM 300323) and not related to familial juvenile hyperuricemic nephropathy (UMOD, OMIM 300323) is a rare gout phenotype characterised by a first flare in adolescence or in young adulthood. While numerous genome wide association studies (GWAS) have been done in classical and late-onset gout, very few studies have been performed in EOG patients. Moreover, until now most genetic studies only assess association between pre-defined single nucleotide polymorphisms (SNP) and gout.ObjectivesOur aim was to identify the genetic variants of clinically confirmed EOG by screening all exons of gout-associated genes with targeted Next-Generation Sequencing (NGS) approach.MethodsTwenty-six urate crystal-proven gout patients with first flare occurring before the age of 30 years were included. Gout history, comorbidities and patient characteristics were recorded. All participants provided written informed consent to genetic analysis. After DNA extraction from total blood samples, the NGS libraries were prepared with surselect QXT (Agilent) and sequencing was performed with miseq (Illumina).The multigene panel included 80 genes described in GWAS and genes involved in rare diseases such as HPRT and UMOD.ResultsTwenty-six patients (24 men, 20 Caucasians, 5 Asians and 1 African) with crystal-proven gout had experienced their first flare at a mean age of 22.8 years [14–29] Gout duration was 11.5 years [1–46] and clinical tophi observed in 9 patients. Mean age was 37.5 [24–69] years and mean body mass index 27.6 kg/m2 [20.1–40.7]. Ten patients were overweight, 5 had obesity, 1 hypertension, 0 diabetes mellitus, 7 dyslipidemia and 10 chronic kidney disease stages 2–4. Mean serum urate level was 527 µmol/L [270–803]. Amongst 26 affected patients, 7 had a molecular anomaly (26.9%). Six patients harboured one rare or novel variant in ABCG2 (three Caucasian patients), ALDH16A1 (two Caucasian patients) and SLC22A11 (one African patient). Two other patients (one Caucasian and one Asian) carried an association of variants in both ABCG2 and ALDH16A1. All variants had a Minor Allele Frequency (MAF) below 0.3% or were never described in public databases. All variant were considered as probably pathogenic according to in silico predictive algorithms. Interestingly, the well-known p.Gln141Lys SNP of ABCG2 was identified in 3 Asian patients (11.5%) at homozygous level.ConclusionsOur finding of very rare and novel pathogenic variants in ABCG2, ALD16H1 and SLC22A11 genes provides better insights of the molecular pathogenesis in early-onset juvenile gout. However, our results also highlight the involvement of yet undetermined genes in this population.Disclosure of InterestNone declared
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