Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype

Combination of reverse transcriptase PCR analysis and immunoglobulin M detection on filter paper blood samples allows diagnostic and epidemiological studies of measles.

As measles control and elimination campaigns progress, laboratory confirmation of clinically diagnosed measles cases becomes increasingly important. However, in many tropical countries collection and storage of clinical specimens for this purpose are logistically complicated. In this study it is shown that blood samples spotted on filter paper are suitable for the laboratory diagnosis of measles using a combination of reverse transcriptase PCR (RT-PCR) analysis and immunoglobulin M (IgM) detection. First, it was shown that in vitro measles virus (MV)-infected cells diluted in human blood and spotted on filter paper can be detected by RT-PCR. Small amounts of infected cells remained detectable after 25 weeks of storage of the filter paper at room temperature, 4 weeks at 37 degrees C, or 2 weeks at 45 degrees C. Subsequently, this RT-PCR was applied to filter paper blood samples collected from 117 clinically diagnosed measles patients in Sudan in 1997 and 1998. Prior laboratory diagnosis had confirmed 90 cases as acute MV infections, while 27 proved to be nonmeasles rash disease cases. Positive RT-PCR signals were detected in filter paper bloo

Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Contains fulltext : 174787.pdf (publisher's version ) (Open Access)Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype

Measurement of the D∗D^* longitudinal polarization in B0→D∗−τ+ντB^0 \to D^{* -}\tau^+\nu_{\tau} decays

The longitudinal polarization fraction of the $D^*$ meson is measured in $B^0 \to D^{* -}\tau^+\nu_{\tau}$ decays, where the $\tau$ lepton decays to three charged pions and a neutrino, using proton-proton collision data collected by the LHCb experiment at center-of-mass energies of 7, 8 and 13 TeV and corresponding to an integrated luminosity of 5 fb$^{-1}$. The $D^*$ polarization fraction $F_L^{D^*}$ is measured in two $q^2$ regions, below and above 7 GeV$^2$/c$^4$, where $q^2$ is defined as the squared invariant mass of the $\tau\nu_{\tau}$ system. The $F_L^{D^*}$ values are measured to be $0.51 \pm 0.07 \pm 0.03$ and $0.35 \pm 0.08 \pm 0.02$ for the lower and higher $q^2$ regions, respectively. The first uncertainties are statistical and the second systematic. The average value over the whole $q^2$ range is: $$F_L^{D^*} = 0.43 \pm 0.06 \pm 0.03.$$ These results are compatible with the Standard Model predictions.The longitudinal polarization fraction of the $D^{*}$ meson is measured in $B^0\to D^{*-}\tau^{+}\nu_{\tau}$ decays, where the $\tau$ lepton decays to three charged pions and a neutrino, using proton-proton collision data collected by the LHCb experiment at center-of-mass energies of 7, 8 and 13 TeV and corresponding to an integrated luminosity of 5 fb$^{-1}$. The $D^{*}$ polarization fraction $F_{L}^{D^{*}}$ is measured in two $q^{2}$ regions, below and above 7 GeV$^{2}/c^{4}$, where $q^{2}$ is defined as the squared invariant mass of the $\tau\nu_{\tau}$ system. The $F_{L}^{D^{*}}$ values are measured to be $0.51 \pm 0.07 \pm 0.03$ and $0.35 \pm 0.08 \pm 0.02$ for the lower and higher $q^{2}$ regions, respectively. The first uncertainties are statistical and the second systematic. The average value over the whole $q^{2}$ range is: $$F_{L}^{D^{*}} = 0.43 \pm 0.06 \pm 0.03.$$ These results are compatible with the Standard Model predictions

Measurement of the D∗D^{*} longitudinal polarization in B0→D∗−τ+ντB^0\to D^{*-}\tau^{+}\nu_{\tau} decays

International audienceThe longitudinal polarization fraction of the $D^{*}$ meson is measured in $B^0\to D^{*-}\tau^{+}\nu_{\tau}$ decays, where the $\tau$ lepton decays to three charged pions and a neutrino, using proton-proton collision data collected by the LHCb experiment at center-of-mass energies of 7, 8 and 13 TeV and corresponding to an integrated luminosity of 5 fb$^{-1}$. The $D^{*}$ polarization fraction $F_{L}^{D^{*}}$ is measured in two $q^{2}$ regions, below and above 7 GeV$^{2}/c^{4}$, where $q^{2}$ is defined as the squared invariant mass of the $\tau\nu_{\tau}$ system. The $F_{L}^{D^{*}}$ values are measured to be $0.51 \pm 0.07 \pm 0.03$ and $0.35 \pm 0.08 \pm 0.02$ for the lower and higher $q^{2}$ regions, respectively. The first uncertainties are statistical and the second systematic. The average value over the whole $q^{2}$ range is: $$F_{L}^{D^{*}} = 0.43 \pm 0.06 \pm 0.03.$$ These results are compatible with the Standard Model predictions