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Bertrand Boisson - One of the best experts on this subject based on the ideXlab platform.
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incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated rpsa exons
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Alexandre Bolze, Bertrand Boisson, Barbara Bosch, Alexander Antipenko, Matthieu Bouaziz, Paul Sackstein, Malik ChakermargotAbstract:Isolated congenital asplenia (ICA) is the only known human developmental defect exclusively affecting a lymphoid organ. In 2013, we showed that private deleterious mutations in the protein-coding region of RPSA, encoding ribosomal protein SA, caused ICA by haploinsufficiency with complete penetrance. We reported seven heterozygous protein-coding mutations in 8 of the 23 kindreds studied, including 6 of the 8 multiplex kindreds. We have since enrolled 33 new kindreds, 5 of which are multiplex. We describe here 11 new heterozygous ICA-causing RPSA protein-coding mutations, and the first two mutations in the 5′-UTR of this gene, which disrupt mRNA splicing. Overall, 40 of the 73 ICA patients (55%) and 23 of the 56 kindreds (41%) carry mutations located in translated or untranslated exons of RPSA. Eleven of the 43 kindreds affected by sporadic disease (26%) carry RPSA mutations, whereas 12 of the 13 multiplex kindreds (92%) carry RPSA mutations. We also report that 6 of 18 (33%) protein-coding mutations and the two (100%) 5′-UTR mutations display incomplete penetrance. Three mutations were identified in two independent kindreds, due to a hotspot or a founder effect. Finally, RPSA ICA-causing mutations were demonstrated to be de novo in 7 of the 23 probands. Mutations in RPSA exons can affect the translated or untranslated regions and can underlie ICA with complete or incomplete penetrance.
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incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated rpsa exons
bioRxiv, 2018Co-Authors: Alexandre Bolze, Bertrand Boisson, Barbara Bosch, Alexander Antipenko, Matthieu Bouaziz, Paul Sackstein, Malik Chakermargot, Vincent Barlogis, Tracy A Briggs, Elena ColinoAbstract:Isolated congenital asplenia (ICA) is the only known human developmental defect exclusively affecting a lymphoid organ. In 2013, we showed that private deleterious mutations in the protein-coding region of RPSA, encoding ribosomal protein SA, caused ICA by haploinsufficiency with complete penetrance. We reported seven heterozygous protein-coding mutations in 8 of the 23 kindreds studied, including 6 of the 8 multiplex kindreds. We have since enrolled 33 new kindreds, 5 of which are multiplex. We describe here eleven new heterozygous ICA-causing RPSA protein-coding mutations, and the first two mutations in the 59-UTR of this gene, which disrupt mRNA splicing. Overall, 40 of the 73 ICA patients (55%) and 23 of the 56 kindreds (41%) carry mutations located in translated or untranslated exons of RPSA. Eleven of the 43 kindreds affected by sporadic disease (26%) carry RPSA mutations, whereas 12 of the 13 multiplex kindreds (92%) carry RPSA mutations. We also report that six of eighteen (33%) protein-coding mutations and the two (100%) 59-UTR mutations display incomplete penetrance. Three mutations were identified in 2 independent kindreds, due to a hotspot or a founder effect. Lastly, RPSA ICA-causing mutations were demonstrated to be de novo in 7 of the 23 probands. Mutations in RPSA exons can affect the translated or untranslated regions and can underlie ICA with complete or incomplete penetrance.
Malik Chakermargot - One of the best experts on this subject based on the ideXlab platform.
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incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated rpsa exons
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Alexandre Bolze, Bertrand Boisson, Barbara Bosch, Alexander Antipenko, Matthieu Bouaziz, Paul Sackstein, Malik ChakermargotAbstract:Isolated congenital asplenia (ICA) is the only known human developmental defect exclusively affecting a lymphoid organ. In 2013, we showed that private deleterious mutations in the protein-coding region of RPSA, encoding ribosomal protein SA, caused ICA by haploinsufficiency with complete penetrance. We reported seven heterozygous protein-coding mutations in 8 of the 23 kindreds studied, including 6 of the 8 multiplex kindreds. We have since enrolled 33 new kindreds, 5 of which are multiplex. We describe here 11 new heterozygous ICA-causing RPSA protein-coding mutations, and the first two mutations in the 5′-UTR of this gene, which disrupt mRNA splicing. Overall, 40 of the 73 ICA patients (55%) and 23 of the 56 kindreds (41%) carry mutations located in translated or untranslated exons of RPSA. Eleven of the 43 kindreds affected by sporadic disease (26%) carry RPSA mutations, whereas 12 of the 13 multiplex kindreds (92%) carry RPSA mutations. We also report that 6 of 18 (33%) protein-coding mutations and the two (100%) 5′-UTR mutations display incomplete penetrance. Three mutations were identified in two independent kindreds, due to a hotspot or a founder effect. Finally, RPSA ICA-causing mutations were demonstrated to be de novo in 7 of the 23 probands. Mutations in RPSA exons can affect the translated or untranslated regions and can underlie ICA with complete or incomplete penetrance.
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incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated rpsa exons
bioRxiv, 2018Co-Authors: Alexandre Bolze, Bertrand Boisson, Barbara Bosch, Alexander Antipenko, Matthieu Bouaziz, Paul Sackstein, Malik Chakermargot, Vincent Barlogis, Tracy A Briggs, Elena ColinoAbstract:Isolated congenital asplenia (ICA) is the only known human developmental defect exclusively affecting a lymphoid organ. In 2013, we showed that private deleterious mutations in the protein-coding region of RPSA, encoding ribosomal protein SA, caused ICA by haploinsufficiency with complete penetrance. We reported seven heterozygous protein-coding mutations in 8 of the 23 kindreds studied, including 6 of the 8 multiplex kindreds. We have since enrolled 33 new kindreds, 5 of which are multiplex. We describe here eleven new heterozygous ICA-causing RPSA protein-coding mutations, and the first two mutations in the 59-UTR of this gene, which disrupt mRNA splicing. Overall, 40 of the 73 ICA patients (55%) and 23 of the 56 kindreds (41%) carry mutations located in translated or untranslated exons of RPSA. Eleven of the 43 kindreds affected by sporadic disease (26%) carry RPSA mutations, whereas 12 of the 13 multiplex kindreds (92%) carry RPSA mutations. We also report that six of eighteen (33%) protein-coding mutations and the two (100%) 59-UTR mutations display incomplete penetrance. Three mutations were identified in 2 independent kindreds, due to a hotspot or a founder effect. Lastly, RPSA ICA-causing mutations were demonstrated to be de novo in 7 of the 23 probands. Mutations in RPSA exons can affect the translated or untranslated regions and can underlie ICA with complete or incomplete penetrance.
Lars C Moeller - One of the best experts on this subject based on the ideXlab platform.
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mycophenolate plus methylprednisolone versus methylprednisolone alone in active moderate to severe graves orbitopathy mingo a randomised observer masked multicentre trial
The Lancet Diabetes & Endocrinology, 2018Co-Authors: George J Kahaly, M Riedl, Jochem Konig, Susanne Pitz, Katharina A Ponto, Tanja Diana, Elena Kampmann, Elisa Kolbe, Anja Eckstein, Lars C MoellerAbstract:Summary Background European guidelines recommend intravenous methylprednisolone as first-line treatment for active and severe Graves' orbitopathy; however, it is common for patients to have no response or have relapse after discontinuation of treatment. We aimed to compare the efficacy and safety of add-on mycophenolate to methylprednisolone in comparison with methylprednisolone alone in patients with moderate-to-severe Graves' orbitopathy. Methods MINGO was an observer-masked, multicentre, block-randomised, centre-stratified trial done in two centres in Germany and two in Italy. Patients with active moderate-to-severe Graves' orbitopathy were randomly assigned to receive intravenous methylprednisolone (500 mg once per week for 6 weeks followed by 250 mg per week for 6 weeks) either alone or with mycophenolate (one 360 mg tablet twice per day for 24 weeks). The prespecified primary endpoints were rate of response (reduction of at least two parameters of a composite ophthalmic index [eyelid swelling, clinical activity score, proptosis, lid width, diplopia, and eye muscle motility] without deterioration in any other parameter) at 12 weeks and rate of relapse (a worsening of symptoms that occurred after a response) at 24 and 36 weeks. Rates of response at week 24 and sustained response at week 36 were added as post-hoc outcomes. Prespecified primary outcomes and post-hoc outcomes were assessed in the modified intention-to-treat population (defined as all patients assigned to treatment who received at least one infusion of methylprednisolone, when outcome data were available), and safety was assessed in all patients who received at least one dose of study drug. This trial is registered with the EU Clinical Trials Register, EUDRACT number 2008-002123-93. Findings 164 patients were enrolled and randomised between Nov 29, 2009, and July 31, 2015. 81 were randomly assigned to receive methylprednisolone alone and 83 to receive methylprednisolone with mycophenolate. In the intention-to-treat population at 12 weeks, responses were observed in 36 (49%) of 73 patients in the monotherapy group and 48 (63%) of 76 patients in the combination group, giving an odds ratio (OR) of 1·76 (95% CI 0·92–3·39, p=0·089). At week 24, 38 (53%) of 72 patients remaining in the monotherapy group and 53 (71%) of 75 patients remaining in the combination therapy group had responded to treatment (2·16, 1·09–4·25, p=0·026). At week 24, relapse occurred in four (11%) of 38 patients in the monotherapy group and four (8%) of 53 patients in the combination group (OR 0·71, 0·17–3·03, p=0·72). At week 36, relapse occurred in an additional three (8%) patients in the monotherapy group and two (4%) patients in the combination group (0·65, 0·12–3·44, p=0·61). At week 36, 31 (46%) of 68 patients in the monotherapy group and 49 (67%) of 73 patients in the combination group had a sustained response (OR 2·44, 1·23–4·82, p=0·011). 23 patients had 24 serious adverse events, with 11 events in ten patients in the combination group and 13 events in 13 patients in the monotherapy group. Mild and moderate (grade 1–2) drug-related adverse events occurred in 16 (20%) of 81 patients receiving monotherapy and 21 (25%) of 83 patients receiving combination therapy (p=0·48). Interpretation Although no significant difference was seen in the rate of response at 12 weeks or rate of relapse at 24 and 36 weeks, post-hoc analysis suggested that addition of mycophenolate to treatment with methylprednisolone improved rate of response to therapy by 24 weeks in patients with active and moderate-to-severe Graves' orbitopathy. Funding Novartis, Germany.
Matthieu Bouaziz - One of the best experts on this subject based on the ideXlab platform.
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incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated rpsa exons
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Alexandre Bolze, Bertrand Boisson, Barbara Bosch, Alexander Antipenko, Matthieu Bouaziz, Paul Sackstein, Malik ChakermargotAbstract:Isolated congenital asplenia (ICA) is the only known human developmental defect exclusively affecting a lymphoid organ. In 2013, we showed that private deleterious mutations in the protein-coding region of RPSA, encoding ribosomal protein SA, caused ICA by haploinsufficiency with complete penetrance. We reported seven heterozygous protein-coding mutations in 8 of the 23 kindreds studied, including 6 of the 8 multiplex kindreds. We have since enrolled 33 new kindreds, 5 of which are multiplex. We describe here 11 new heterozygous ICA-causing RPSA protein-coding mutations, and the first two mutations in the 5′-UTR of this gene, which disrupt mRNA splicing. Overall, 40 of the 73 ICA patients (55%) and 23 of the 56 kindreds (41%) carry mutations located in translated or untranslated exons of RPSA. Eleven of the 43 kindreds affected by sporadic disease (26%) carry RPSA mutations, whereas 12 of the 13 multiplex kindreds (92%) carry RPSA mutations. We also report that 6 of 18 (33%) protein-coding mutations and the two (100%) 5′-UTR mutations display incomplete penetrance. Three mutations were identified in two independent kindreds, due to a hotspot or a founder effect. Finally, RPSA ICA-causing mutations were demonstrated to be de novo in 7 of the 23 probands. Mutations in RPSA exons can affect the translated or untranslated regions and can underlie ICA with complete or incomplete penetrance.
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incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated rpsa exons
bioRxiv, 2018Co-Authors: Alexandre Bolze, Bertrand Boisson, Barbara Bosch, Alexander Antipenko, Matthieu Bouaziz, Paul Sackstein, Malik Chakermargot, Vincent Barlogis, Tracy A Briggs, Elena ColinoAbstract:Isolated congenital asplenia (ICA) is the only known human developmental defect exclusively affecting a lymphoid organ. In 2013, we showed that private deleterious mutations in the protein-coding region of RPSA, encoding ribosomal protein SA, caused ICA by haploinsufficiency with complete penetrance. We reported seven heterozygous protein-coding mutations in 8 of the 23 kindreds studied, including 6 of the 8 multiplex kindreds. We have since enrolled 33 new kindreds, 5 of which are multiplex. We describe here eleven new heterozygous ICA-causing RPSA protein-coding mutations, and the first two mutations in the 59-UTR of this gene, which disrupt mRNA splicing. Overall, 40 of the 73 ICA patients (55%) and 23 of the 56 kindreds (41%) carry mutations located in translated or untranslated exons of RPSA. Eleven of the 43 kindreds affected by sporadic disease (26%) carry RPSA mutations, whereas 12 of the 13 multiplex kindreds (92%) carry RPSA mutations. We also report that six of eighteen (33%) protein-coding mutations and the two (100%) 59-UTR mutations display incomplete penetrance. Three mutations were identified in 2 independent kindreds, due to a hotspot or a founder effect. Lastly, RPSA ICA-causing mutations were demonstrated to be de novo in 7 of the 23 probands. Mutations in RPSA exons can affect the translated or untranslated regions and can underlie ICA with complete or incomplete penetrance.
Jelle Matthijnssens - One of the best experts on this subject based on the ideXlab platform.
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characterization of a novel g3p 3 rotavirus isolated from a lesser horseshoe bat a distant relative of feline canine rotaviruses
Journal of Virology, 2013Co-Authors: Biao He, F Yang, W Yang, Y Zhang, Yunlong Feng, J Zhou, Y Li, N Li, Jelle Matthijnssens, H ZhangAbstract:ABSTRACT Bats are considered important animal reservoirs for many viruses pathogenic to humans. An approach based on viral metagenomics was used to study gut specimens from 78 insectivorous bats in Yunnan Province, China. Seventy-four reads were found to be related to group A rotavirus (RVA). Further reverse transcription-PCR screening and viral isolation on cell cultures confirmed the presence of a novel RVA strain, named RVA/Bat-tc/MSLH14/2012/G3P[3], in 1 (6%) of 16 lesser horseshoe bats. Full genomic sequencing analyses showed that MSLH14 possessed the genotype constellation G3-P[3]-I8-R3-C3-M3-A9-N3-T3-E3-H6, which is akin to human and animal rotaviruses believed to be of feline/canine origin. Phylogenetic analysis indicated that VP7 was most closely related to bovine RVA strains from India, whereas VP4 was most closely related to an unusual human RVA strain, CMH222, with animal characteristics isolated in Thailand. The remaining gene segments were only distantly related to a range of animal RVA strains, most of which are believed to be related to feline/canine RVAs. Experimental infection showed that bat RVA strain MSLH14 was highly pathogenic to suckling mice, causing 100% mortality when they were inoculated orally with a titer as low as 5 × 10 2 50% tissue culture infective doses. As this virus is not closely related to any known RVA strain, it is tempting to speculate that it is a true bat RVA strain rather than a virus transmitted between species. However, further screening of bat populations, preferably juvenile animals, will be crucial in determining whether or not this virus is widely distributed in the bat population.
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equine g3p 3 rotavirus strain e3198 related to simian rrv and feline canine like rotaviruses based on complete genome analyses
Veterinary Microbiology, 2013Co-Authors: S Mino, Jelle Matthijnssens, Marc Van Ranst, A Badaracco, Lorena Garaicoechea, Mark Zeller, Elisabeth Heylen, M Barrandeguy, Viviana ParrenoAbstract:Abstract Equine group A rotavirus (RVA) strains are the most important cause of gastroenteritis in equine neonates and foals worldwide, and G3P[12] and G14P[12] are epidemiologically the most important genotypes. The genotype constellation of an unusual Argentinean G3P[3] RVA strain (RVA/Horse-wt/E3198/2008/G3P[3]) detected in fecal samples of a diarrheic foal in 2008 was shown to be G3–P[3]–I3–R3–C3–M3–A9–N3–T3–E3–H6. Each of these genotypes has been found typically in feline and canine RVA strains, and the genotype constellation is reminiscent to those of Cat97-like RVA strains. However, the phylogenetic analyses revealed only a distant relationship between E3198 and known feline, canine and feline/canine-like human RVA strains. Surprisingly, a rather close relationship was found between E3198 and simian RVA strains RVA/Simian-tc/USA/RRV/1975/G3P[3] for at least 5 gene segments. RRV is believed to be a reassortant between a bovine-like RVA strain and a RVA strains distantly related to feline/canine RVA strains. These analyses indicate that E3198 is unlikely to be of equine origin, and most likely represents a RVA interspecies transmitted virus, possibly in combination with one or more reassortments, from a feline, canine or related host species to a horse. Further studies are in progress to evaluate if this strain was a single interspecies transmission event, or if this strain started to circulate in the equine population.
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genotype constellation and evolution of group a rotaviruses infecting humans
Current Opinion in Virology, 2012Co-Authors: Jelle Matthijnssens, Marc Van RanstAbstract:Numerous rotavirus group A (RVA) strains with distinct G-genotype and P-genotype combinations have been described infecting humans worldwide. However, the increasing amount of complete RVA genome data which have become available, suggest that only RVA strains with 2 discrete genotype constellations have been successful in sustaining infection of humans worldwide over longer periods of time. Those genotype constellations have been designated I1-R1-C1-M1-A1-N1-T1-E1-H1 and I2-R2-C2-M2-A2-N2-T2-E2-H2 and are also known as Wa-like and DS-1-like, respectively. RVAs of other genotype constellations which were able to spread to a limited extent in the human population are AU-1-related RVA strains (I3-R3-C3-M3-A3/A12-N3-T3-E3-H3/H6) in combination with G3P[9] or G12P[9], and neonatal G10P[11] RVA strains in India (bovine × human Wa-like reassortants). On the basis of the analysis of complete genomes, it is suggested that the overall genetic diversity of epidemiologically widespread human RVA strains is more limited than generally assumed. This conclusion has consequences for how we look at host range restriction and the criteria according to which the effectiveness of RVA universal mass vaccination programs is assessed.
