Identification of a Novel Variant in EARS2 Associated with a Severe Clinical Phenotype Expands the Clinical Spectrum of LTBL

The EARS2 nuclear gene encodes mitochondrial glutamyl-tRNA synthetase, a member of the class I family of aminoacyl-tRNA synthetases (aaRSs) that plays a crucial role in mitochondrial protein biosynthesis by catalyzing the charging of glutamate to mitochondrial tRNA(Glu). Pathogenic EARS2 variants have been associated with a rare mitochondrial disorder known as leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL). The targeted sequencing of 150 nuclear genes encoding respiratory chain complex subunits and proteins implicated in the oxidative phosphorylation (OXPHOS) function was performed. The oxygen consumption rate (OCR), and the extracellular acidification rate (ECAR), were measured. The enzymatic activities of Complexes I-V were analyzed spectrophotometrically. We describe a patient carrying two heterozygous EARS2 variants, c.376C>T (p.Gln126*) and c.670G>A (p.Gly224Ser), with infantile-onset disease and a severe clinical presentation. We demonstrate a clear defect in mitochondrial function in the patient's fibroblasts, suggesting the molecular mechanism underlying the pathogenicity of these EARS2 variants. Experimental validation using patient-derived fibroblasts allowed an accurate characterization of the disease-causing variants, and by comparing our patient's clinical presentation with that of previously reported cases, new clinical and radiological features of LTBL were identified, expanding the clinical spectrum of this disease

Nieuwe strategieën van pro-actief soortenbeleid: proefdraaien met een gebiedsgerichte aanpak; verslag werkatelier 28 april 2004

Het soortenbeleid in het natuurbeheer wordt in brede kring als onvoldoende effectief beschouwd. In het werkatelier verslag zijn de resultaten uiteengezet van deelnemers die hebben nagedacht over nieuwe strategieën van pro-actief soortenbeleid. Het idee is dat de soortenzorg voor een groot deel ruimtelijk en regionaal zal moeten worden uitgewerkt. Daarnaast is een generiek beleid nodig voor soorten die verspreid voorkomen. Voor beide zoekrichtingen is het nodig om te verbreden naar ander beleid en nieuwe doelgroepen. Deelnemers hebben deze denkwijze getoetst en uitgewerkt in nieuwe strategieën. Voor de case Waterland zijn 3 verbredingstrategieën bedacht aan de hand van specifieke soorten evenals voor de case Zuid-Limburg. Voor generieke soorten zijn 4 strategien bedacht om actoren in beweging te krijgen

Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder.

Mitochondrial protein synthesis requires charging mt-tRNAs with their cognate amino acids by mitochondrial aminoacyl-tRNA synthetases, with the exception of glutaminyl mt-tRNA (mt-tRNAGln). mt-tRNAGln is indirectly charged by a transamidation reaction involving the GatCAB aminoacyl-tRNA amidotransferase complex. Defects involving the mitochondrial protein synthesis machinery cause a broad spectrum of disorders, with often fatal outcome. Here, we describe nine patients from five families with genetic defects in a GatCAB complex subunit, including QRSL1, GATB, and GATC, each showing a lethal metabolic cardiomyopathy syndrome. Functional studies reveal combined respiratory chain enzyme deficiencies and mitochondrial dysfunction. Aminoacylation of mt-tRNAGln and mitochondrial protein translation are deficient in patients' fibroblasts cultured in the absence of glutamine but restore in high glutamine. Lentiviral rescue experiments and modeling in S. cerevisiae homologs confirm pathogenicity. Our study completes a decade of investigations on mitochondrial aminoacylation disorders, starting with DARS2 and ending with the GatCAB complex

SMDT1 variants impair EMRE-mediated mitochondrial calcium uptake in patients with muscle involvement

Ionic calcium (Ca2+) is a key messenger in signal transduction and its mitochondrial uptake plays an important role in cell physiology. This uptake is mediated by the mitochondrial Ca2+ uniporter (MCU), which is regulated by EMRE (essential MCU regulator) encoded by the SMDT1 (single-pass membrane protein with aspartate rich tail 1) gene. This work presents the genetic, clinical and cellular characterization of two patients harbouring SMDT1 variants and presenting with muscle problems. Analysis of patient fibroblasts and complementation experiments demonstrated that these variants lead to absence of EMRE protein, induce MCU subcomplex formation and impair mitochondrial Ca2+ uptake. However, the activity of oxidative phosphorylation enzymes, mitochondrial morphology and membrane potential, as well as routine/ATP-linked respiration were not affected. We hypothesize that the muscle-related symptoms in the SMDT1 patients result from aberrant mitochondrial Ca2+ uptake

Comparison of innovation policies in selected European, Asian and Pacific Rim countries: how best to optimise innovation governance in New Zealand?

The technology users’ innovation (TUI) research programme aims to identify the conditions under which socio-technical networks best foster technology development, adoption and commercialisation, and thereby contribute to improved innovation outcomes and innovation governance in New Zealand. The main research objective of this report was to compare innovation policy across selected European and Pacific Rim countries in order to assess how best to optimise innovation policy in New Zealand. Two assessments of National Systems of Innovation (NIS) policies settings were made, each using a different framework of analysis for the selected case study countries (20 and 21 cases respectively). The sample included selected European and Asian countries, Australia and New Zealand. From the European experts assessments, results from comparing New Zealand with the European Innovation Leaders shows that there is potential to improve NIS in New Zealand by giving attention to: • Innovation policy strategic intelligence: strategic exercises, advisory bodies, foresights, evaluations, peer reviews, benchmarking, NIS studies capacity building within agencies in charge of policy design and implementation. • Public private partnerships and knowledge transfer: via competence centres and joint public-private organisation oriented towards innovation, clusters, networks and poles with businesses as main drivers the provision of science parks and incubators providing knowledge transfer incentives such as science-industry bridging organisations, university transfer offices, cooperative programmes, funding schemes, and research commercialisation schemes. Private R&D innovation: direct and indirect support for private R&D via subsidies, loans and tax incentives subsidies and vouchers, advisory services and management support for innovation adaptation of curricula and training programmes to further innovation, and financial and non-financial support for human resources for innovation companies demand stimulation policies, such as innovative public procurement and lead market initiatives. Entrepreneurship and new firm creation spin offs and start up programmes including finance, infrastructure, advisory schemes, brokerage services, business plans, competitions to support new technology based firms (NTBFs), entrepreneurship training such as courses and initiatives in basic or continuing education to enhance entrepreneurial spirit and facilitate innovation company formation risk and venture capital to include guarantee mechanisms, co-funding of venture capital companies and business angel networks. From the New Zealand expert assessments, results from comparing New Zealand with the European Innovation Leaders shows that there is potential to improve NIS in New Zealand by: Improving high-level horizontal agency framework, that is, the NIS provides a strong unifying approach that supports policy guided by government’s strategic plan for the nation. Implementing a tangible commitment to horizontal coherence so that NIS policies are complementary. • Establishing a clear national vision for innovation. • Implementing and developing the proposed changes in governance to achieve: improved vertical coherence so that NIS policies are implemented in the way they are intended, and improved stakeholder and business involvement in policy making and priority setting. From the two assessments made, Finland and Denmark are consistently seen as Innovation Leaders and there is a need to consider their innovation policy settings as potentially relevant to New Zealand.Funding for the research reported here was provided by the New Zealand Foundation for Research, Science and Technology, under contract number LINX 0801