Mutations in the urocanase gene UROC1 are associated with urocanic aciduria

[EN] Urocanase is an enzyme in the histidine pathway encoded by the UROC1 gene. This report describes the first putative mutations, p. L70P and p.R450C, in the coding region of the UROC1 gene in a girl with urocanic aciduria presenting with mental retardation and intermittent ataxia. Computed (in silico) predictions, protein expression studies and enzyme activity assays suggest that none of the mutations can produce a fully functional enzyme. The p. L70P substitution, which probably implies the disruption of an alpha-helix in the N-terminus, would alter its properties and therefore, its function. The p.R450C change would render impossible any interaction between urocanase and its substrate and would loss its enzyme activity. Consequently, these studies suggest that both mutations could alter the correct activity of urocanase, which would explain the clinical and biochemical findings described in this patient.We are grateful to the patient for her kind collaboration. We are indebted to Dr C Marco-Marín for the in silico structural studies. CIBERER is an initiative of the Instituto de Salud Carlos III. This work was supported by grants from the Fondo de Investigación Sanitaria (PI051318 and PI070548).Espinós-Armero, CÁ.; Pineda, M.; Martínez-Rubio, D.; Aída Ormazabal; María Antonia Vilaseca; Leo J. M. Spaapen; Palau, F.... (2009). Mutations in the urocanase gene UROC1 are associated with urocanic aciduria. Journal of Medical Genetics. 46(6):407-411. https://doi.org/10.1136/jmg.2008.06063240741146

CblE type of homocystinuria due to methionine synthase reductase deficiency : functional correction by minigene expression

The cblE type of homocystinuria is a rare autosomal recessive disorder caused by impaired reductive activation of methionine synthase. Although earlier biochemical studies proposed that the methionine synthase enzyme might be activated by two different reducing systems, mutations were reported in only the methionine synthase reductase gene (MTRR) in cblE patients. The pathogenicity of MTRR mutations, however, has not yet been tested functionally. We report on nine patients of European origin affected by the cblE type of homocystinuria. They presented between 2 weeks and 3 years of age (median age 4 weeks) with anemia, which was macrocytic in only three patients, and with neurological involvement in all but two cases. Bone marrow examination performed in seven patients showed megaloblastic changes in all but one of them. All patients exhibited moderate to severe hyperhomocysteinemia (median plasma total homocysteine [Hcy] 92 mumol/L, range 44-169), while clearly reduced methionine was observed only in four cases. Pathogenic mutations were identified in both parental alleles of the MTRR gene in all patients. Five known (c.903+469T<C, c.1361C<T, c.1459G<A, c.1557-4_1557+3del7, and c.1622_1623dupTA) and three novel mutations (c.7A<T, c.1573C<T, and c.1953-6_1953-2del5) were detected. Importantly, transfection of fibroblasts of cblE patients with a wild-type MTRR minigene expression construct resulted in a significant approximately four-fold increase of methionine synthesis, indicating correction of the enzyme defect. Our study shows a link between a milder predominantly hematological presentation and homozygosity for the c.1361C<T mutation, but no other obvious genotype-phenotype correlation. The identification of mutations in the MTRR gene, together with restoration of methionine synthesis following MTRR minigene expression in cblE cells confirms that this disease is caused by defects in the MTRR gene

紀伊国 和歌山藩札 銀札1匁

日本銀行金融研究所所蔵藩札資料番号：ⅢAエドa1-57-3-61(1)科学研究費助成事業（研究成果公開促進費）で電子化を実施データベースの名称：藩札等に関する統合データベース課題番号：18HP8038藩札の利用に関するお問い合わせ：藩札画像の転載（出版物・HP等）に際しては、日本銀行貨幣博物館への申請手続きが必要です。詳しくは貨幣博物館ホームページ（http://www.imes.boj.or.jp/cm/service/）をご覧ください

A multicentric study to evaluate the use of relative retention times in targeted proteomics

Despite the maturity reached by targeted proteomic strategies, reliable and standardized protocols are urgently needed to enhance reproducibility among different laboratories and analytical platforms, facilitating a more widespread use in biomedical research. To achieve this goal, the use of dimensionless relative retention times (iRT), defined on the basis of peptide standard retention times (RT), has lately emerged as a powerful tool. The robustness, reproducibility and utility of this strategy were examined for the first time in a multicentric setting, involving 28 laboratories that included 24 of the Spanish network of proteomics laboratories (ProteoRed-ISCIII). According to the results obtained in this study, dimensionless retention time values (iRTs) demonstrated to be a useful tool for transferring and sharing peptide retention times across different chromatographic set-ups both intra- and inter-laboratories. iRT values also showed very low variability over long time periods. Furthermore, parallel quantitative analyses showed a high reproducibility despite the variety of experimental strategies used, either MRM (multiple reaction monitoring) or pseudoMRM, and the diversity of analytical platforms employed. BIOLOGICAL SIGNIFICANCE: From the very beginning of proteomics as an analytical science there has been a growing interest in developing standardized methods and experimental procedures in order to ensure the highest quality and reproducibility of the results. In this regard, the recent (2012) introduction of the dimensionless retention time concept has been a significant advance. In our multicentric (28 laboratories) study we explore the usefulness of this concept in the context of a targeted proteomics experiment, demonstrating that dimensionless retention time values is a useful tool for transferring and sharing peptide retention times across different chromatographic set-ups.All laboratories from Spain are members of ProteoRed (Plataforma de Recursos Biomoleculares y Bioinformáticos) and are supported by grant PT13/0001 funded by Instituto de Salud Carlos III (ISCIII) and FEDER.S

Overcome imposter syndrome: Contribute to working groups and build strong networks

Scientific working groups bring together experts from different disciplines and perspectives to tackle the “wicked problems” facing natural systems and society. Yet participants can feel overwhelmed or inadequate in groups within academic environments, which tends to be most acute at early career stages and in people from systematically marginalized backgrounds. Such feelings can block innovation that would otherwise arise from gaining the full spectrum of unique perspectives, knowledge and skills from a group. Drawing on personal experiences and relevant literature, we identify ten contribution strategies, ranging from generating ideas, analyzing data, and producing visuals to supporting facilitation. Next, we share approaches for an inclusive and supportive process, considering the roles of both participants and leads. Generating the most productive and relevant outcomes from working groups requires engaging the full team in a constructive and supportive environment. We advocate that adopting inclusive approaches that respect the diversity of personality types and perspectives will lead to more innovative solutions to achieve conservation and sustainability goals